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A multicenter study on the clinical outcome of chorioamnionitis in preterm infants

Published:February 17, 2009DOI:https://doi.org/10.1016/j.ajog.2008.11.034

      Objective

      The purpose of this study was to examine the effects of clinical maternal chorioamnionitis on morbidity and mortality rates among infants who are at < 33 weeks of gestation, adjusted for patient characteristics that included admission neonatal illness severity (Score for Neonatal Acute Physiology, version II; SNAP-II).

      Study Design

      With multivariate logistic regression analysis, prospectively collected hospital outcomes from the Canadian Neonatal Network of singleton infants with birth gestational age of < 33 weeks and clinical chorioamnionitis were compared retrospectively with nonexposed infants.

      Results

      Of 3094 infants, 477 infants (15.4%) who were exposed to clinical chorioamnionitis had significantly higher admission SNAP-II scores. Bivariate analysis revealed that the neonatal mortality rate was increased significantly in the chorioamnionitis group (10.6% vs 6.1%). Multivariate regression analysis with adjustment for illness severity indicated that chorioamnionitis was associated with an increased risk of early sepsis (odds ratio, 5.54; 95% confidence interval, 2.87-10.69) and severe intraventricular hemorrhage (odds ratio, 1.62; 95% confidence interval, 1.17-2.24) but not neonatal death.

      Conclusion

      Preterm infants who are exposed to clinical chorioamnionitis have an increased risk of early-onset sepsis and severe intraventricular hemorrhage.

      Key words

      Chorioamnionitis is an acute infection of the placental membranes. It refers to both the clinical syndrome of intrauterine infection and the histologic processes that occur. Chorioamnionitis is associated with 50% of preterm deliveries at < 30 weeks of gestation,
      • Newton E.R.
      Chorioamnionitis and intraamniotic infection.
      which accounts for 70% of perinatal deaths and 50% of long-term neurologic morbidity.
      • Goldenberg R.L.
      • Hauth J.C.
      • Andrews W.W.
      Intrauterine infection and preterm delivery.
      For Editors' Commentary, see Table of Contents
      There is increasing evidence that preterm infants are particularly vulnerable to adverse effects of chorioamnionitis. Preterm infants who are exposed to clinical chorioamnionitis are 2-3 times more likely to have neonatal problems, compared with those without exposure to clinical chorioamnionitis.
      • Alexander J.M.
      • Gilstrap L.C.
      • Cox S.M.
      • McIntire D.M.
      • Leveno K.J.
      Clinical chorioamnionitis and the prognosis for very low birth weight infants.
      Intrauterine exposure to infection is known to induce a fetal inflammatory response, and the resultant elevated levels of proinflammatory cytokines are associated with an increased incidence of preterm birth and lung and brain injury.
      • Yoon B.H.
      • Romero R.
      • Yang S.H.
      • et al.
      Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia.
      • Yoon B.H.
      • Romero R.
      • Kim K.S.
      • et al.
      A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia.
      These inflammatory cytokines have been associated with fetal and neonatal brain injury, which include periventricular leukomalacia (PVL)
      • Alexander J.M.
      • Gilstrap L.C.
      • Cox S.M.
      • McIntire D.M.
      • Leveno K.J.
      Clinical chorioamnionitis and the prognosis for very low birth weight infants.
      • Rocha G.
      • Proença E.
      • Quintas C.
      • Rodrigues T.
      • Guimarães H.
      Chorioamnionitis and brain damage in the preterm newborn.
      intraventricular hemorrhage (IVH),
      • Alexander J.M.
      • Gilstrap L.C.
      • Cox S.M.
      • McIntire D.M.
      • Leveno K.J.
      Clinical chorioamnionitis and the prognosis for very low birth weight infants.
      • Rocha G.
      • Proença E.
      • Quintas C.
      • Rodrigues T.
      • Guimarães H.
      Chorioamnionitis and brain damage in the preterm newborn.
      • Ogunyemi D.
      • Murillo M.
      • Jackson U.
      • Hunter N.
      • Alperson B.
      The relationship between placental histopathology findings and perinatal outcome in preterm infants.
      • Salafia C.M.
      • Minior V.K.
      • Rosenkrantz T.S.
      • et al.
      Maternal, placental and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks gestation.
      • Dammann O.
      • Leviton A.
      Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn.
      • Verma U.
      • Tejani N.
      • Klein S.
      • et al.
      Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate.
      • Weeks J.W.
      • Reynolds L.
      • Taylor D.
      • Lewis J.
      • Wan T.
      • Gall S.A.
      Umbilical cord blood interleukin-6 levels and neonatal morbidity.
      and bronchopulmonary dysplasia (BPD).
      • Alexander J.M.
      • Gilstrap L.C.
      • Cox S.M.
      • McIntire D.M.
      • Leveno K.J.
      Clinical chorioamnionitis and the prognosis for very low birth weight infants.
      • Rocha G.
      • Proença E.
      • Quintas C.
      • Rodrigues T.
      • Guimarães H.
      Chorioamnionitis and brain damage in the preterm newborn.
      A metaanalysis of observational studies revealed a significant association between clinical chorioamnionitis, cystic PVL, and cerebral palsy.
      • Wu Y.W.
      • Escobar G.J.
      • Grether J.K.
      • Croen L.A.
      • Greene J.D.
      • Newman T.B.
      Chorioamnionitis and cerebral palsy in term and near-term infants.
      There is controversy in the literature regarding whether chorioamnionitis increases the risk of lung injury that results in BPD. A few studies have shown an increased risk of BPD in infants who are exposed to chorioamnionitis,
      • Rocha G.
      • Proença E.
      • Quintas C.
      • Rodrigues T.
      • Guimarães H.
      Chorioamnionitis and brain damage in the preterm newborn.
      • Salafia C.M.
      • Minior V.K.
      • Rosenkrantz T.S.
      • et al.
      Maternal, placental and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks gestation.
      • Lau J.
      • Magee F.
      • Qiu Z.
      • Houbé J.
      • Von Dadelszen P.
      • Lee S.K.
      Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than chorioamnionitis displaying a maternal inflammatory response only.
      • Fung G.
      • Bawden K.
      • Chow P.
      • Yu V.
      Chorioamnionitis and outcome in extremely preterm infants.
      • Van Marter L.J.
      • Dammann O.
      • Allred E.N.
      • et al.
      Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants.
      • Watterberg K.L.
      • Demers L.M.
      • Scott S.M.
      • Murphy S.
      Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.
      • Viscardi R.M.
      • Muhumuza C.K.
      • Rodriguez A.
      • et al.
      Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants.
      but others showed little or no change.
      • Richardson B.S.
      • Wakim E.
      • daSilva O.
      • Walton J.
      Preterm histologic chorioamnionitis: impact on cord gas and pH values and neonatal outcome.
      • Kent A.
      • Lomas F.
      • Hurrion E.
      • Dahlstrom J.E.
      Antenatal steroids may reduce adverse neurological outcome following chorioamnionitis: neurodevelopmental outcome and chorioamnionitis in premature infants.
      • Redline R.W.
      • Wilson-Costello D.
      • Hack M.
      Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants.
      • Elimian A.
      • Verma U.
      • Beneck D.
      • Cipriano R.
      • Visintainer P.
      • Tejani N.
      Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes.
      • Dexter S.C.
      • Pinar H.
      • Malee M.P.
      • Hogan J.
      • Carpenter M.W.
      • Vohr B.R.
      Outcome of very low birth weight infants with histopathologic chorioamnionitis.
      The incidence of chorioamnionitis increases with decreasing gestational age.
      • Lahra M.M.
      • Jeffery H.E.
      A fetal response to chorioamnionitis is associated with early survival after preterm birth.
      Correction for gestational age may accurately estimate the actual contribution of chorioamnionitis to acute neonatal morbidity and long-term sequelae.
      Score for Neonatal Acute Physiology, version II (SNAP-II) is a validated neonatal illness severity score that has been shown to predict neonatal death and adverse neonatal outcomes.
      • Richardson D.K.
      • Corcoran J.D.
      • Escobar G.L.
      • Lee S.K.
      SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores.
      • Chien L.Y.
      • Whyte R.
      • Thiessen P.
      • Walker R.
      • Brabyn D.
      • Lee S.K.
      SNAP-II predicts severe intraventricular hemorrhage and chronic lung disease in the neonatal intensive care unit.
      It is unclear whether the association between chorioamnionitis and adverse neonatal morbidity is related to higher illness severity after birth or whether it occurs independently of illness severity. Previous studies are mostly retrospective and from single centers
      • Alexander J.M.
      • Gilstrap L.C.
      • Cox S.M.
      • McIntire D.M.
      • Leveno K.J.
      Clinical chorioamnionitis and the prognosis for very low birth weight infants.
      • Ogunyemi D.
      • Murillo M.
      • Jackson U.
      • Hunter N.
      • Alperson B.
      The relationship between placental histopathology findings and perinatal outcome in preterm infants.
      • Salafia C.M.
      • Minior V.K.
      • Rosenkrantz T.S.
      • et al.
      Maternal, placental and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks gestation.
      • Verma U.
      • Tejani N.
      • Klein S.
      • et al.
      Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate.
      • Weeks J.W.
      • Reynolds L.
      • Taylor D.
      • Lewis J.
      • Wan T.
      • Gall S.A.
      Umbilical cord blood interleukin-6 levels and neonatal morbidity.
      • Lau J.
      • Magee F.
      • Qiu Z.
      • Houbé J.
      • Von Dadelszen P.
      • Lee S.K.
      Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than chorioamnionitis displaying a maternal inflammatory response only.
      • Fung G.
      • Bawden K.
      • Chow P.
      • Yu V.
      Chorioamnionitis and outcome in extremely preterm infants.
      • Van Marter L.J.
      • Dammann O.
      • Allred E.N.
      • et al.
      Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants.
      • Watterberg K.L.
      • Demers L.M.
      • Scott S.M.
      • Murphy S.
      Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.
      • Viscardi R.M.
      • Muhumuza C.K.
      • Rodriguez A.
      • et al.
      Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants.
      • Richardson B.S.
      • Wakim E.
      • daSilva O.
      • Walton J.
      Preterm histologic chorioamnionitis: impact on cord gas and pH values and neonatal outcome.
      and have not been adjusted for illness severity. The objective of our study was to examine the effects of clinical chorioamnionitis on neonatal morbidity and death independent of patient characteristics that include illness severity in a large multicenter cohort of preterm infants.

      Materials and Methods

      Study populations

      The study cohort included all singleton infants with birth gestational age < 33 weeks without congenital anomalies who were admitted to 24 tertiary neonatal intensive care units (NICUs) that were participating in the Canadian Neonatal Network between January 1, 2005, and December 31, 2006.

      Data collections

      Standardized data were collected by the Canadian Neonatal Network.
      • Lee S.K.
      • McMillan D.D.
      • Ohlsson A.
      • et al.
      Variations in practice and outcomes in the Canadian NICU Network: 1996-1997.
      Trained research assistants used a standard manual of protocols and definitions to enter data prospectively from patient charts into laptop computers with a customized data entry program with built-in error checks. Data were transmitted electronically to the Canadian Neonatal Network Coordinating Centre, which is located at the Integrated Centre for Care Advancement through Research (Edmonton, Alberta) where data management and analyses were performed under the direction of a regionally represented steering committee. Patient information is collected until death or discharge from the NICU. Ethics approval was obtained from the institutional review boards of all participating institutions.

      Definitions

      Indices of neonatal outcome were defined according to the Canadian Neonatal Network Data Abstractor Manual.
      • Lee S.K.
      • McMillan D.D.
      • Ohlsson A.
      • et al.
      Variations in practice and outcomes in the Canadian NICU Network: 1996-1997.
      Chorioamnionitis was defined as inflammation of amnion and chorion. The diagnosis of chorioamnionitis was made by the attending obstetrician, based on the presence of accepted clinical signs which included foul-smelling amniotic fluid, maternal fever during labor, uterine tenderness (without another cause), fetal tachycardia, and maternal leukocytosis. These clinical signs were recorded in the clinical chart; the presence of > 1 clinical sign was needed. Gestational age was defined as the best obstetric estimate based on early prenatal ultrasound examination, obstetric examination, and obstetric history; if the postnatal pediatric estimate of gestation differed from the obstetric estimate by > 2 weeks, the pediatric estimate was used. The Canadian Neonatal Network database incorporates a neonatal illness severity score entitled SNAP-II. The SNAP-II score was calculated within 12 hours of admission to an NICU and quantifies 6 physiologic variables: temperature, blood pressure, PaO2/fraction of inspired oxygen ratio, serum pH, the presence of seizures, and urine output.
      • Richardson D.K.
      • Corcoran J.D.
      • Escobar G.L.
      • Lee S.K.
      SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores.
      The score can range from 0-115; higher scores reflect more disturbances in neonatal physiologic condition.
      • Richardson D.K.
      • Corcoran J.D.
      • Escobar G.L.
      • Lee S.K.
      SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores.
      Respiratory distress syndrome (RDS) was defined as the presence of respiratory symptoms, such as grunting and chest retraction, typical chest radiograph findings, and/or treatment with surfactant and the need for mechanical ventilation for > 24 hours. Necrotizing enterocolitis was defined according to Bell's criteria (stage ≥ 2)
      • Bell M.J.
      • Ternberg J.L.
      • Feigin R.D.
      • et al.
      Neonatal necrotizing enterocolitis: therapeutic decisions based on clinical staging.
      and was classified as medical (ie, clinical symptoms and signs, such as abdominal distension, increased prefeed gastric aspirate and bloody stools, plus evidence of pneumatosis on abdominal radiograph) or surgical (histologic evidence of necrotizing enterocolitis on surgical specimen of intestine). Patent ductus arteriosus (PDA) was defined as clinical diagnosis plus treatment with indomethacin, surgical ligation, or both. Early-onset neonatal sepsis was defined as positive single-organism cultures from blood or cerebrospinal fluid that were obtained from an infant with signs or risk factors for sepsis during the first 48 hours after birth. BPD was defined as supplemental oxygen dependency at 36 weeks of corrected gestational age.
      • Shennan A.T.
      • Dunn M.S.
      • Ohlsson A.
      • Lennox K.
      • Hoskins E.M.
      Abnormal pulmonary outcomes in preterm infants: prediction from oxygen requirement in the neonatal period.
      If an infant was discharged home or transferred to another hospital before 36 weeks of corrected gestational age on supplemental oxygen, a diagnosis of BPD was recorded. Oxygen use was governed by the oxygen saturation targets, which may vary among Canadian Neonatal Network NICUs. IVH was defined according to the Canadian Pediatric Society criteria from a head ultrasonogram, which was performed at < 14 days of life.
      Fetus and Newborn CommitteeCanadian Pediatric Society
      Routine screening cranial ultrasound examinations for the prediction of long term neurodevelopmental outcomes in preterm infants.
      When there was more than one report or if there was bilateral IVH, the highest grade was used. Intraparenchymal hemorrhage (with or without IVH) was classified as grade 4 IVH. Grades 3 and 4 IVH are considered as severe IVH. PVL was defined as parenchymal echo densities/lucencies around the ventricles from head ultrasound scans that were performed after 21 days of life. Retinopathy of prematurity (ROP) was defined according to the International Classification for Retinopathy of Prematurity.
      American Academy of Pediatrics, committee members: an International Committee for the classification of the late stages of retinopathy of prematurity
      An international classification of retinopathy of prematurity.
      Severe ROP was defined as ROP stage > 2. Major morbidity was defined as the presence of any ≥ 1 of BPD, necrotizing enterocolitis, severe IVH, or severe ROP.

      Data analysis

      Statistical analyses were performed with STATA software (version 9; Stata Corp, College Station, TX). Infants with clinical chorioamnionitis were compared with those infants without evidence of chorioamnionitis. Categorical variables were analyzed with χ2 and the Fisher exact tests. Continuous variables were analyzed by comparisons of means, except when the data were not distributed normally and/or when the variances were significantly different, in which case the Mann-Whitney U test or median test was used. Covariates with significant association (P < .05) to chorioamnionitis in the baseline perinatal characteristics were considered to be possible confounders and were included in the model for regression analyses. We conducted the multivariate logistic regression analyses in 2 steps: (1) the use of only baseline population risk factors and (2) the addition of the SNAP-II. The first step identified which risk factors were independent predictors of the outcome; the second step determined whether these effects were mediated independently or through increased illness severity. P < .05 was considered statistically significant. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for outcomes.

      Results

      Of the 3466 eligible singleton infants who were admitted to the 24 NICUs, chorioamnionitis data were available for 3094 infants (89%). Of the 3094 infants, 477 infants (15.4%) had clinical chorioamnionitis. Table 1 shows the demographic characteristics of the infants. The mean gestational age of infants in the chorioamnionitis group was significantly lower than those who were born to mothers without chorioamnionitis (27.7 ± 2.7 weeks vs 29.1 ± 2.4 weeks of gestation; P < .001). The mean birthweight was also significantly lower among infants with chorioamnionitis (1174 ± 439 g vs 1347 ± 460 g; P < .001). Infants in the chorioamnionitis group were more likely to have vaginal birth and antenatal steroid exposure and less likely to be born to mothers with hypertension. The median admission SNAP-II score was significantly higher among infants in the chorioamnionitis group.
      TABLE 1Characteristics of infants with and without clinical chorioamnionitis
      CharacteristicChorioamnionitis (n = 477)No chorioamnionitis (n = 2617)P value
      Gestational age (wk)
      Mean ± SD;
      27.7 ± 2.729.1 ± 2.4< .001
      Birthweight (g)
      Mean ± SD;
      1174 ± 4391347 ± 460< .001
      Male (%)4954.11
      Vaginal delivery (%)6045< .001
      Antenatal steroid (%)88.477.3< .001
      Maternal hypertension (%)3.824.9< .001
      Maternal diabetes mellitus (%)5.67.5.17
      Apgar at 5 min
      Median (interquartile range).
      7 (6-9)8 (7-9).004
      SNAP-II score
      Median (interquartile range).
      10 (5-20)8 (0-14)< .001
      SNAP-II, Score for Neonatal Acute Physiology, version II.
      Soraisham. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009.
      a Mean ± SD;
      b Median (interquartile range).
      Table 2 compares infant outcomes between the groups with and without chorioamnionitis. Infants in the chorioamnionitis group had significantly higher rates of RDS, PDA, BPD, severe IVH (grades 3 and 4), ROP stage > 2, and neonatal sepsis. Approximately 4.8% of infants who were delivered of women with chorioamnionitis experienced early-onset sepsis, compared with 0.9% of infants who were delivered of women without chorioamnionitis (P < .001). Of the 3094 infants in the study cohort, ultrasound scans for IVH were available for 2245 infants (72.5%). Among the chorioamnionitis group, 81 of 366 infants (22.1%) had severe IVH, compared with 225 of 1879 infants (11.9%) without chorioamnionitis (P < .0001). The proportion of infants who did not have an ultrasound report was 23.2% in the chorioamnionitis group and 28.2% in the group without chorioamnionitis. Infants who did not have available cranial ultrasound reports were larger in size (mean birthweight, 1604 g vs 1213 g), were more mature (mean gestational age, 30.2 weeks vs 28.4 weeks), and had lower SNAP-II scores (median score, 5 vs 9). These infants also had lower incidence of RDS (41% vs 73%) and PDA (6% vs 19%). There was no difference in the antenatal steroid exposure rates between the 2 groups (80.2% vs 82.6%). Of the 3094 infants in the study cohort, 212 infants (6.8%) died during the hospital stay. The neonatal mortality rate was significantly higher in the chorioamnionitis group (10.6%), compared with the group without chorioamnionitis (6.1%). The rates of survival without any major morbidity (ie, BPD, NEC, IVH grades 3 and 4, or ROP stage > 2) were significantly lower in the chorioamnionitis group, compared with the group without chorioamnionitis (62.2% vs 72.6%; P < .001).
      TABLE 2Percentage comparison of neonatal outcomes between infants with and without clinical chorioamnionitis
      Variable (%)Chorioamnionitis (n = 477)No chorioamnionitis (n = 2617)P value
      RDS6963.01
      Necrotizing enterocolitis4.63.4.24
      PDA3021.7< .001
      Early-onset sepsis4.80.9< .001
      Severe IVH22.111.9< .001
      PVL9.18.1.64
      BPD2721.03
      ROP stage > 213.78.6.026
      Mortality rate (%)10.66.1< .003
      Survival without major morbidity (%)62.272.6< .001
      BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity.
      Soraisham. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009.
      Table 3 shows the relationship between chorioamnionitis and neonatal outcomes after adjustment for baseline population characteristics, which included gestational age, birthweight, vaginal birth, antenatal steroid exposure, maternal hypertension, and Apgar score at 5 minutes by multivariate logistic regression analysis. Chorioamnionitis was associated independently with early sepsis (OR, 5.84; 95% CI, 3.03-11.25) and severe IVH (OR, 1.60; 95% CI, 1.16-2.21). We then added SNAP-II to the model as a dichotomous variable (Table 4). We found similar results when the SNAP-II score was used as a continuous variable. Chorioamnionitis remained an independent predictor of early sepsis (OR, 5.54; 95% CI, 2.87-10.69) and severe IVH (OR, 1.62; 95% CI, 1.17-2.24), but not for NICU death (OR, 0.98; 95% CI, 0.65-1.50). Severe IVH was associated with chorioamnionitis, independently of early-onset sepsis (OR, 1.57; 95% CI, 1.13-2.18).
      TABLE 3Clinical chorioamnionitis and neonatal outcomes by multivariate logistic regression
      Adjustment included gestational age, birthweight, vaginal delivery, antenatal steroid and maternal hypertension, and Apgar score at 5 minutes, but not SNAP-II in the model;
      without adjustment for illness severity
      OutcomeAdjusted OR95% CIP value
      RDS0.850.66-1.09.21
      Necrotizing enterocolitis1.130.67-1.90.63
      PDA0.750.56-1.00.053
      Early-onset sepsis5.843.03-11.25.0001
      Severe IVH1.601.16-2.21.004
      PVL0.900.53-1.53.71
      BPD0.840.57-1.23.38
      ROP1.140.71-1.84.56
      Any major morbidity
      Major morbidity (ie, BPD, necrotizing enterocolitis, IVH grade ≥ 3, ROP stage 2).
      0.930.72-1.21.62
      Death0.970.64-1.46.90
      BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity.
      Soraisham. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009.
      a Adjustment included gestational age, birthweight, vaginal delivery, antenatal steroid and maternal hypertension, and Apgar score at 5 minutes, but not SNAP-II in the model;
      b Major morbidity (ie, BPD, necrotizing enterocolitis, IVH grade ≥ 3, ROP stage 2).
      TABLE 4Clinical chorioamnionitis and neonatal outcomes by multivariate logistic regression that were adjusted for baseline perinatal characteristics and illness severity
      OutcomeAdjusted OR95% CIP value
      RDS0.830.64-1.07.16
      Necrotizing enterocolitis1.130.67-1.91.62
      PDA0.750.56-1.00.053
      Early-onset sepsis5.542.87-10.69< .001
      Severe IVH1.621.17-2.24.003
      PVL0.900.53-1.54.724
      BPD0.850.58-1.24.40
      ROP1.170.72-1.88.51
      Any major morbidity0.930.72-1.21.61
      Death0.980.65-1.50.96
      BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity.
      Soraisham. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009.

      Comment

      To the best of our knowledge, this is the largest multicenter cohort study to describe neonatal outcomes after clinical chorioamnionitis and to control for illness severity at birth in preterm infants. Our study shows that clinical chorioamnionitis is associated with RDS, PDA, BPD, and ROP; the association is related to lower gestational age and birthweight. Infants who are exposed to clinical chorioamnionitis are sicker (higher SNAP-II) at birth, and SNAP-II scores have been shown to be reliable predictors for neonatal morbidity and death.
      • Richardson D.K.
      • Corcoran J.D.
      • Escobar G.L.
      • Lee S.K.
      SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores.
      • Chien L.Y.
      • Whyte R.
      • Thiessen P.
      • Walker R.
      • Brabyn D.
      • Lee S.K.
      SNAP-II predicts severe intraventricular hemorrhage and chronic lung disease in the neonatal intensive care unit.
      However, the association of clinical chorioamnionitis with increased incidence of early-onset sepsis and severe IVH is independent of gestational age and birthweight and is not mediated through increased illness severity. These findings are consistent with previous reports. Elimian et al
      • Elimian A.
      • Verma U.
      • Beneck D.
      • Cipriano R.
      • Visintainer P.
      • Tejani N.
      Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes.
      reported that chorioamnionitis increases major perinatal morbidity through its association with preterm delivery but is associated independently with neonatal death. This study did not consider illness severity at birth. In contrast, Alexander et al
      • Alexander J.M.
      • Gilstrap L.C.
      • Cox S.M.
      • McIntire D.M.
      • Leveno K.J.
      Clinical chorioamnionitis and the prognosis for very low birth weight infants.
      reported that exposure to chorioamnionitis was not an independent predictor for neonatal mortality, which is similar to our findings.
      Alexander et al
      • Alexander J.M.
      • Gilstrap L.C.
      • Cox S.M.
      • McIntire D.M.
      • Leveno K.J.
      Clinical chorioamnionitis and the prognosis for very low birth weight infants.
      and Verma et al
      • Verma U.
      • Tejani N.
      • Klein S.
      • et al.
      Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate.
      also reported increased IVH and PVL among infants who were born to women with chorioamnionitis. A metaanalysis of observational studies by Wu et al
      • Wu Y.W.
      • Escobar G.J.
      • Grether J.K.
      • Croen L.A.
      • Greene J.D.
      • Newman T.B.
      Chorioamnionitis and cerebral palsy in term and near-term infants.
      reported that clinical chorioamnionitis is associated with cystic PVL and cerebral palsy. In contrast, Sarkar et al
      • Sarkar S.
      • Kaplan C.
      • Wiswell T.E.
      • Spitzer A.R.
      Histological chorioamnionitis and the risk of early intraventricular hemorrhage in infants born ≤ 28 weeks gestation.
      did not find an increased risk of early IVH with chorioamnionitis in a prospective study of 68 preterm infants. They speculated that the reduction in early IVH (< 72 hours) in their study may be related to the inhibition of early inflammatory responses by prenatal steroid treatment that was received by 93% of the infants. In our study, chorioamnionitis was associated independently with IVH but not cystic PVL. Because 88% of the infants in the clinical chorioamnionitis group received antenatal steroids, our results do not support the speculation of Sarkar et al.
      • Sarkar S.
      • Kaplan C.
      • Wiswell T.E.
      • Spitzer A.R.
      Histological chorioamnionitis and the risk of early intraventricular hemorrhage in infants born ≤ 28 weeks gestation.
      There may be several reasons that chorioamnionitis is associated with the increased risk of intraventricular bleeding and brain injury. Chorioamnionitis leads to the release of vasoactive inflammatory mediators that are able to mediate alteration in the blood-brain barrier, intravascular cell adhesion, coagulation, and thrombosis. This can lead to endothelial damage within fragile germinal matrix capillaries and subependymal venous networks that results in bleeding.
      • De Reuck J.L.
      Cerebral angioarchitecture and perinatal brain lesions in premature and full-term infants.
      • Loc H.C.
      The “lost autoregulation hypothesis” and brain lesions in the newborn: an update.
      The proposed mechanisms of neurotoxicity that are associated with proinflammatory cytokines include: (1) a direct cytolytic effect on neurons and oligodendrocytes precursors (either through in situ cytokine production or through systemic cytokine crossing blood-brain barrier); (2) the induction of excitatory amino acid release; (3) the increased caspase activity, which results in amplified apoptosis; (4) abnormalities in the coagulation cascade; and (5) fetal hypotension. Proinflammatory cytokines that are produced as a consequence of intrauterine infection are associated with the development of cranial ultrasound abnormalities in infants who are born at < 28 weeks of gestation.
      • Viscardi R.M.
      • Muhumuza C.K.
      • Rodriguez A.
      • et al.
      Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants.
      Previous studies have reported that chorioamnionitis is associated with sepsis in the infant,
      • Alexander J.M.
      • Gilstrap L.C.
      • Cox S.M.
      • McIntire D.M.
      • Leveno K.J.
      Clinical chorioamnionitis and the prognosis for very low birth weight infants.
      • Ogunyemi D.
      • Murillo M.
      • Jackson U.
      • Hunter N.
      • Alperson B.
      The relationship between placental histopathology findings and perinatal outcome in preterm infants.
      • Lau J.
      • Magee F.
      • Qiu Z.
      • Houbé J.
      • Von Dadelszen P.
      • Lee S.K.
      Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than chorioamnionitis displaying a maternal inflammatory response only.
      which might have contributed to continuing exposure to inflammatory factors of neonatal origin. We found a significantly increased risk of culture-positive early sepsis in the chorioamnionitis group. However, considering the widespread use of antenatal antibiotics, the diagnosis of early-onset sepsis that is based on blood culture may underestimate the true incidence of sepsis.
      It has been hypothesized that a genetic predisposition to cytokine functional polymorphism may also play a role in the determination of which infants who are exposed to intrauterine infection have brain damage. Nelson et al
      • Nelson K.B.
      • Dambrosia J.M.
      • Iovannisci D.M.
      • Cheng S.
      • Grether J.K.
      • Lammer E.
      Genetic polymorphisms and cerebral palsy in very preterm infants.
      found differential expression of various single genetic polymorphisms among infected infants. Individuals with tumor necrosis factor-α promoter region polymorphism demonstrate an increased production of cytokine and increased risk of preterm rupture of membrane. Genetic factors, in part, may determine the extent of inflammation that occurs in the face of maternal infection.
      A few studies have shown an increased risk of BPD in infants who are exposed to chorioamnionitis
      • Rocha G.
      • Proença E.
      • Quintas C.
      • Rodrigues T.
      • Guimarães H.
      Chorioamnionitis and brain damage in the preterm newborn.
      • Salafia C.M.
      • Minior V.K.
      • Rosenkrantz T.S.
      • et al.
      Maternal, placental and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks gestation.
      • Lau J.
      • Magee F.
      • Qiu Z.
      • Houbé J.
      • Von Dadelszen P.
      • Lee S.K.
      Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than chorioamnionitis displaying a maternal inflammatory response only.
      • Fung G.
      • Bawden K.
      • Chow P.
      • Yu V.
      Chorioamnionitis and outcome in extremely preterm infants.
      • Van Marter L.J.
      • Dammann O.
      • Allred E.N.
      • et al.
      Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants.
      • Watterberg K.L.
      • Demers L.M.
      • Scott S.M.
      • Murphy S.
      Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.
      • Viscardi R.M.
      • Muhumuza C.K.
      • Rodriguez A.
      • et al.
      Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants.
      ; other studies show little or no difference.
      • Richardson B.S.
      • Wakim E.
      • daSilva O.
      • Walton J.
      Preterm histologic chorioamnionitis: impact on cord gas and pH values and neonatal outcome.
      • Kent A.
      • Lomas F.
      • Hurrion E.
      • Dahlstrom J.E.
      Antenatal steroids may reduce adverse neurological outcome following chorioamnionitis: neurodevelopmental outcome and chorioamnionitis in premature infants.
      • Redline R.W.
      • Wilson-Costello D.
      • Hack M.
      Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants.
      • Elimian A.
      • Verma U.
      • Beneck D.
      • Cipriano R.
      • Visintainer P.
      • Tejani N.
      Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes.
      • Dexter S.C.
      • Pinar H.
      • Malee M.P.
      • Hogan J.
      • Carpenter M.W.
      • Vohr B.R.
      Outcome of very low birth weight infants with histopathologic chorioamnionitis.
      Intrauterine exposure to infection may also be associated with a decreased incidence of RDS in preterm babies by way of a postulated mechanism of the increased endogenous fetal cortisol, which facilitates fetal lung maturation.
      • Watterberg K.L.
      • Scott S.M.
      • Naeye R.L.
      Chorioamnionitis, cortisol and acute lung disease in very low birth weight infants.
      • Shimoya K.
      • Taniguchi T.
      • Matsuzaki N.
      • et al.
      Chorioamnionitis decreased incidence of respiratory distress syndrome by elevating fetal interleukin-6 serum concentration.
      The limitations of the present study include the clinical nature of the diagnosis of chorioamnionitis, based on maternal and neonatal chart documentation. Information on histologic chorioamnionitis and/or funisitis was not available. Histologic chorioamnionitis is related inversely to gestational age
      • Lahra M.M.
      • Jeffery H.E.
      A fetal response to chorioamnionitis is associated with early survival after preterm birth.
      ; however, there is a disparity between rates of clinical chorioamnionitis and histologic changes in the placenta, with histologic chorioamnionitis being diagnosed more frequently in high-risk and preterm pregnancies, particularly at extremely early gestations.
      • Goldenberg R.L.
      • Hauth J.C.
      • Andrews W.W.
      Intrauterine infection and preterm delivery.
      • Lahra M.M.
      • Jeffery H.E.
      A fetal response to chorioamnionitis is associated with early survival after preterm birth.
      • Sweet M.P.
      • Hodgman J.E.
      • Pena I.
      • et al.
      Two year outcome of infants weighing 600 grams or less at birth and born 1994 through 1998.
      Some infants were transferred to other hospitals, and outcomes data were not available for some of them. In our study, infants who did not have cranial ultrasound reports were larger in size, were more mature and had lower SNAP-II scores, and had lower rates of RDS and PDA. Hence, they were also less likely to have IVH. It is also possible that the bigger and less ill babies are more likely to be transferred earlier and/or have their diagnostic tests (such as ultrasound scans) omitted from their care. The present study cannot reliably predict the magnitude of associations between exposure to chorioamnionitis and severe IVH. Because a diagnosis of BPD was recorded if an infant was discharged home or transferred to another hospital still on supplemental oxygen, the incidence of BPD was overestimated. Infants who are transferred to community hospitals are screened for ROP at those hospitals and routinely transferred back to the NICU if a diagnosis of stage ≥ 3 ROP is made. Although it is possible that an infant with stage ≥ 3 ROP might be transferred to an NICU different from the referring unit (and is then not captured in our database), this is rare because neonatal care in Canada is highly regionalized, with each tertiary level NICU serving a distinct geographic region.
      Infants who are exposed to clinical chorioamnionitis are at higher risk for brain injury, which may have serious long-term consequences.
      • Wu Y.W.
      • Escobar G.J.
      • Grether J.K.
      • Croen L.A.
      • Greene J.D.
      • Newman T.B.
      Chorioamnionitis and cerebral palsy in term and near-term infants.
      Prolonging the period until delivery may have adverse long-term consequences for these infants.
      • Dammann O.
      • Leviton A.
      • Gappa M.
      • Dammann C.E.
      Lung and brain damage in preterm newborns, and their association with gestational age, prematurity subgroup, infection/inflammation and long term outcome.
      • Yoon B.H.
      • Jun J.K.
      • Romero R.
      • et al.
      Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy.
      Once the diagnosis of chorioamnionitis is made, a fetus may benefit from immediate delivery rather than treatment of mothers with tocolytics and antibiotics. Appropriate timing of delivery of the infant in the presence of clinical chorioamnionitis must be further explored in prospective clinical trials.

      Acknowledgments

      We thank the following members of the Canadian Neonatal Network: Anne Synnes, British Columbia Children's Hospital, Vancouver, British Columbia; Todd Sorokan, Royal Columbian Hospital, New Westminster, British Columbia; Cherrie Tan-Dy, Victoria General Hospital, Victoria, British Columbia; Nalini Singhal, Foothills Medical Centre, Calgary, Alberta; Abraham Ninan, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, Royal University Hospital, Saskatoon, Saskatchewan; Molly Seshia,Winnipeg Health Sciences Centre, Winnipeg, Manitoba; Gerarda Cronin, St. Boniface General Hospital, Winnipeg, Manitoba; Kenneth Tan, Hamilton Health Sciences Centre, Hamilton, Ontario; David Lee, St Joseph's Health Centre, London, Ontario; Andrew James, Hospital for Sick Children, Toronto, Ontario; Arne Ohlsson, Mount Sinai Hospital, Toronto, Ontario; Michael Dunn, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario; Maxine Clarke, Kingston General Hospital, Kingston, Ontario; Lajos Kovacs, Jewish General Hospital, Montreal, Quebec; Bruno Piedboeuf, Centre Hospitalier Universitaire de Quebec, Sainte Foy, Quebec; Patricia Riley, Montreal Children's Hospital, Montreal, Quebec; Sophie Nadeau, Royal Victoria Hospital, Montreal, Quebec; Doug McMillan, IWK Health Centre, Halifax, Nova Scotia; Rody Canning, Moncton Hospital, Moncton, New Brunswick; Barbara Bulleid, Doctor Everret Chalmers Hospital, Fredericton, New Brunswick; Cecil Ojah, St. John Regional Hospital, Saint John, New Brunswick; Khalid Aziz, Janeway Children's Health and Rehabilitation Centre, St. John's, Newfoundland.

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