Background
In patients with preterm premature rupture of membranes, intrauterine inflammation
and/or infection is frequently present, can lead to fetal inflammatory response syndrome,
and is associated with adverse neonatal outcome. Clinical decision making requires
balancing the potential benefits of pregnancy prolongation against the risk of intrauterine
infection. Diagnostic tests in maternal serum are of moderate prediction value and
amniocentesis is an invasive procedure. Therefore, markers obtained noninvasively
would be helpful in patients with expectant management.
Objectives
To determine the predictive values of amniotic fluid interleukin-6 and tumor necrosis
factor-α in vaginal secretions for fetal inflammatory response syndrome and/or histologic
funisitis and for adverse neonatal outcome in patients with preterm premature rupture
of membranes.
Study Design
In this prospective multicenter case-control study, vaginal secretions were sampled
daily with a noninvasive method from 99 women with preterm premature rupture of membranes
and expectant management. Amniotic fluid interleukin-6 and tumor necrosis factor-α
were measured by 2 different immunoassays (an automated chemiluminescent enzyme immunoassay
and a lateral flow immunoassay). After delivery, patients were divided into a control
or a fetal inflammatory response syndrome group according to neonatal interleukin-6
in cord plasma and/or the presence of funisitis. Univariate and multivariate regression
analyses were performed and prediction models were developed by calculating receiver
operating characteristic curves.
Results
Gestational age at delivery was lower and latency period was longer in the fetal inflammatory
response syndrome group compared to the control group. The strongest risk factor for
composite adverse neonatal outcome was fetal inflammatory response syndrome (odds
ratio, 2.48; confidence interval, 1.40–4.38). The median concentrations of amniotic fluid
interleukin-6 and tumor necrosis factor-α in vaginal secretions were significantly
higher in the fetal inflammatory response group compared to the control group in both
immunoassays (P < .001). The area under the curve of the clinical reference model (including common
clinical parameters) was 0.66. Adding interleukin-6 and tumor necrosis factor-α into
the model improved the area under the curve to 0.92 (in both assays, interleukin-6
IMMULITE and QuickLine); 0.87 (tumor necrosis factor-α IMMULITE) and 0.94 (tumor necrosis
factor-α QuickLine), respectively.
Conclusion
The strongest risk factor for worse neonatal outcome (composite neonatal outcome)
was fetal inflammatory response syndrome. Amniotic fluid interleukin-6 and tumor necrosis
factor-α seem to be good predictors for fetal inflammatory response syndrome and for
histologic funisitis and may improve the clinical management of patients with preterm
premature rupture of membranes. The noninvasive technique of sampling amniotic fluid
from vaginal secretions facilitates daily measurements and bedside assessment of cytokines
and is in this respect preferable to invasive amniocentesis.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to American Journal of Obstetrics & GynecologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The fetal inflammatory response syndrome.Am J Obstet Gynecol. 1998; : 194-202
- The fetal inflammatory response syndrome.Clin Obstet Gynecol. 2007; 50: 652-683
- A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and Gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes.Am J Obstet Gynecol. 1993; 169: 839-851
- Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome.Matern Fetal Neonatal Med. 2002; 11: 18-25
- Microbial invasion of the amniotic cavity in premature rupture of membranes.Clin Obstet Gynecol. 1991; 34: 769-778
- Histologic inflammation in the maternal and fetal compartments in a rabbit model of acute intra-amniotic infection.Am J Obstet Gynecol. 2000; 183: 1088-1093
- The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates.Am J Reprod Immunol. 2013; 70: 265-284
- Acute histologic chorioamnionitis is a risk factor for adverse neonatal outcome in late preterm birth after preterm premature rupture of membranes.PLoS One. 2013; 8: e79941
- Preterm premature rupture of membranes.Obstet Gynecol. 2003; 10: 178-193
- A systemic inflammatory response is followed by spontaneous onset of preterm parturition.Am J Obstet Gynecol. 1998; 179: 186-193
- Differences in amniotic fluid and maternal serum cytokine levels in early midtrimester women without evidence of infection.Cytokine. 2008; 44: 78-84
- Interleukin-6 and interleukin-1 receptor antagonist in amniotic fluid and cord blood in patients with pre-term, premature rupture of membranes.Int J Gynaecol Obstet. 2002; 77: 123-129
- The diagnostic performance of the Mass Restricted (MR) score in the identification of microbial invasion of the amniotic cavity or intra-amniotic inflammation is not superior to amniotic fluid interleukin-6.J Matern Fetal Neonatal Med. 2014; 27: 757-769
- Bedside assessment of amniotic fluid interleukin-6 in preterm prelabor rupture of membranes.Am J Obstet Gynecol. 2014; 211: 385.e1-385.e9
- A point of care test for interleukin-6 in amniotic fluid in preterm prelabor rupture of membranes: a step toward the early treatment of acute intra-amniotic inflammation/infection.J Matern Fetal Neonatal Med. 2015; 23: 1-8
- Detection of intraamniotic inflammation in fresh and processed amniotic fluid samples with the interleukin-6 point of care test.Am J Obstet Gynecol. 2015; 213: 435-436
- Rapid evaluation of the absence of inflammation after rupture of membranes.J Matern Fetal Neonatal Med. 2014; 27: 865-869
- Vaginal fluid IL-6 and IL-8 levels in pregnancies complicated by preterm prelabor membrane ruptures.Matern Fetal Neonatal Med. 2015; 28: 392-398
- Predictive value of combined cervicovaginal cytokines and gestational age at sampling for intra-amniotic infection in preterm premature rupture of membranes.Acta Obstet Gynecol Scand. 2013; 92: 517-524
- The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis.Am J Obstet Gynecol. 2000; 183: 1124-1129
- Maternal serum cytokines in preterm premature rupture of membranes.Obstet Gynecol. 2007; 109: 121-127
- Changes in maternal blood inflammatory markers as a predictor of chorioamnionitis: a prospective multicenter study.Am J Reprod Immunol. 2015; 73: 79-90
- Accuracy of C-reactive protein determination in predicting chorioamnionitis and neonatal infection in pregnant women with premature rupture of membranes: a systematic review.Eur J Obstet Gynecol Reprod Biol. 2009; 147: 124-129
- Compartmentalization of acute phase reactants Interleukin-6, C-Reactive Protein and Procalcitonin as biomarkers of intra-amniotic infection and chorioamnionitis.Cytokine. 2015; 76: 236-243
- The antibiotic treatment of PPROM study: systemic maternal and fetal markers and perinatal outcomes.Am J Obstet Gynecol. 2012; 206: 145.e1-145.e9
- Management of clinical chorioamnionitis at term.Am J Obstet Gynecol. 2004; 191: 1-2
- Intrapartum management of premature rupture of membranes: effect on cesarean delivery rate.Obstet Gynecol. 2011; 118: 1247-1254
- Inflammatory responses in the placenta and umbilical cord.Semin Fetal Neonatal Med. 2006; 11: 296-301
- Inflammatory response in acute chorioamnionitis.Semin Fetal Neonatal Med. 2012; 17: 20-25
- Components of the systemic fetal inflammatory response syndrome as predictors of impaired neurologic outcomes in children.Am J Obstet Gynecol. 2003; 188: 1438-1444
- Acute funisitis is associated with distinct changes in fetal hematologic profile.J Matern Fetal Neonatal Med. 2015; 28: 588-593
- Cord blood levels of interleukin-6 and interleukin-8 for the immediate diagnosis of early-onset infection in premature infants.Biol Neonate. 2001; 80: 118-123
- Plasma levels and gene expression of granulocyte colony-stimulating factor, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 in neonatal early onset sepsis.Pediatr Res. 1998; 44: 469-477
- Effective biomarkers for diagnosis of neonatal sepsis.J Ped Infect Dis. 2014; 3: 234-245
- Prenatal inflammation is associated with adverse neonatal outcomes.Am J Obstet Gynecol. 2014; 210: 450.e1-450.e10
- Outcomes of expectantly managed pregnancies with multiple gestations and preterm premature rupture of membranes prior to 26 weeks.Am J Obstet Gynecol. 2015; 212: 215.e1-215.e9
- Neonatal necrotizing enterocolitis.N Engl J Med. 1978; 298: 281-282
- Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight less than 1500g.J Pediatr. 1978; 92: 529-534
- ACOG Practice Bulletin No. 139: premature rupture of membranes. Clinical management guidelines for obstetrician-gynecologists.Obstet Gynecol. 2013; 139: 918-930
- Intraamniotic inflammation in women with preterm prelabor rupture of membranes.PLoS One. 2015;24; 10: e0133929
- Cervical fluid IL-6 and IL-8 levels in pregnancies complicated by preterm prelabor rupture of membranes.J Matern Fetal Neonatal Med. 2015; 28: 134-140
- Detection of interleukin-6 in vaginal secretions of women with preterm premature rupture of membranes and its association with neonatal infection: a rapid immunochromatographic test.Am J Obstet Gynecol. 2005; 192: 140-145
- A rapid interleukin-6 bedside test for the identification of intra-amniotic inflammation in preterm labor with intact membranes.J Matern Fetal Neonatal Med. 2015; 23: 1-11
- A point of care test for the determination of amniotic fluid interleukin-6 and the chemokine CXCL-10/IP-10.J Matern Fetal Neonatal Med. 2015; 28: 1510-1519
- A novel method for collecting vaginal pool for fetal lung maturity studies.Am J Obstet Gynecol. 2009; 201: 408.e1-408.e4
- Maternal serum and amniotic fluid cytokines in patients with preterm premature rupture of membranes with and without intrauterine infection.Int J Gynaecol Obstet. 2002; 79: 209-215
Article info
Publication history
Published online: January 29, 2016
Accepted:
January 22,
2016
Received in revised form:
December 30,
2015
Received:
October 13,
2015
Footnotes
The authors report no conflict of interest.
This study was supported, in part, by the German Federal Ministry of Education and Research (BMBF; BioChancePlus 0313174).
Cite this article as: Kunze M, Klar M, Morfeld CA, et al. Cytokines in noninvasively obtained amniotic fluid as predictors of fetal inflammatory response syndrome. Am J Obstet Gynecol 2016;215:96.e1-8.
Identification
Copyright
© 2016 Elsevier Inc. All rights reserved.
