Acta Obstet Gynecol Scand 2003; 82: 543--549 Printed in Denmark.

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Copyright # Acta Obstet Gynecol Scand 2003

Acta Obstetricia et Gynecologica Scandinavica

ISSN 0001-6349

ORIGINAL ARTICLE

Maternal serum interleukin-6, interleukin-8, tumor necrosis factor-a and interferon-g in preterm labor
AHMED M. BAHAR1, HASHIM W. GHALIB2, RIYAD A. MOOSA2, ZAKI M. S. ZAKI1, CHET THOMAS3
AND

OSMAN A. NABRI4

From the 1Department of Obstetrics and Gynecology, College of Medicine and Medical Sciences, King Khalid University, Saudi Arabia, 2Department of Microbiology and Parasitology, College of Medicine and Medical Sciences, King Khalid University, Saudi Arabia, 3Department of Pathological Sciences, School of Veterinary Medicine, University of Wisconsin, USA and 4Department of Neonatology, Abha Maternity Hospital, Abha, Saudi Arabia

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Acta Obstet Gynecol Scand 82 2003

Background. To find out whether preterm labor is associated with raised maternal serum concentrations of interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-g) and whether the measurement of these cytokines can be used to detect early intrauterine infection in preterm labor. Methods. Cross-sectional study: 77 women in preterm labor, 47 controls of healthy preterm women not in labor and 19 women in term labor. The serum cytokines levels were measured by enzyme-linked immunosorbent assay (ELISA). The newborns of women who were in labor were followed up for evidence of infection. Differences between groups were tested using analysis of variance, Students t-test and w2-test. Results. There was no significant difference in the concentration of all the cytokines measured between the different groups. No statistical difference was found in the concentration of the cytokines between women in preterm labor with ruptured membranes and those with intact membranes. There was also no difference found in the concentration of cytokines between women whose newborns had positive bacterial culture and those with negative culture. There was a positive correlation between the concentrations of IL-6, IL-8 and TNF-a. Conclusion. Serum levels of interleukin-6, interleukin-8 and tumor necrosis factor-a were not increased in preterm labor compared to normal control women. There is doubt regarding the usefulness of maternal serum measurement of these cytokines for the detection of early fetal infection in preterm labor, but this needs further evaluation. Key words: preterm labor; interleukin-6; interleukin-8; tumor necrosis factor-a; interferon-g; proinflammatory cytokines Submitted 13 August, 2002 Accepted 14 January, 2003

Preterm labor is a major cause of perinatal morbidity and mortality (1,2). It complicates 510% of all deliveries (1,3). Infection is the underlying cause of preterm labor and preterm prelabor rupAbbreviations: IL: interleukin; TNF-a: tumor necrosis factor alpha; IFN-g: interferon gamma; pPROM: preterm prelabor rupture of the membranes; NICU: neonatal intensive care unit; PBS: phosphate-buffered saline, WBC:white blood count.

ture of the membranes (pPROM) in about 25 40% of the cases (46). Bacterial invasion of the choriodecidual space activates the decidua and fetal membranes to produce cytokines including interleukin (IL)-1, IL-6, IL-8, granulocyte colonystimulating factor and tumor necrosis factor alpha (TNF-a) (7,8). These proinammatory cytokines may induce the synthesis and release of prostaglandins that stimulate uterine contractions and metalloproteinases that soften the cervix and
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A. M. Bahar et al. 2436 weeks of gestation, not in labor, recruited from our antenatal clinic at random (n 47). Group 3 consisted of women who were in normal term labor (n 19). Labor was diagnosed when the woman had regular painful uterine contractions occurring at least twice every 10 min for at least 1 h, confirmed by cardiotocography and/or cervical effacement or dilatation. Preterm labor was defined as labor at 36 weeks of gestation. Gestational age was assessed by the last menstrual period and/or from ultrasound fetal measurements carried out in the first or early second trimester when available. Women who had more than one fetus, evidence of preeclampsia, urinary tract or respiratory tract infections, fever, were currently using antibiotics or who presented with clinical signs of chorioamnionitis, which is defined as maternal fever with temperature ! 37.8 C and any of uterine tenderness, malodorous vaginal discharge, maternal tachycardia > 100 beats/min, fetal tachycardia > 160 beats/min or maternal leukocytosis (WBC > 15 000 cells/mm3), were excluded from the study. Twenty-six out of 103 women admitted in preterm labor during the study period were not included in the study; 14 women because of the exclusion criteria mentioned above and 12 because they were not approached by the staff. Methods Blood (10 mL) was withdrawn in a plain tube immediately upon admission of women in labor and before any treatment was given. Blood from preterm women not in labor was withdrawn in the antenatal clinic. The blood was immediately centrifuged for 20 min at 400g at 4 C and the separated serum was stored at 70 C. Full blood count and urine examination were also performed for all women as a routine investigation upon admission. Women in preterm labor whose gestational age was below 34 weeks were given rectal indomethacin to suppress labor, and betamethasone 12 mg intramuscularly 12 hourly for 24 h to guard against respiratory distress syndrome. All women with preterm rupture of the membranes received antibiotics, mostly erythromycin. After delivery all newborns who were 34 weeks, those who were delivered by caesarean section and those who showed signs of respiratory difficulties, low Apgar scores or suspected of having infection were admitted to the neonatal intensive care unit (NICU) for observation and routine investigations. Those suspected of having infection were bacteriologically

weaken the chorioamniotic membranes leading to their rupture (911). Intrauterine infection also leads to microbial invasion of the fetus resulting in neonatal sepsis, interventricular hemorrhage (12), brain white matter lesions, cerebral palsy (13) and bronchopulmonary dysplasia (14) or even death. IL-6 and TNF-a may be involved in the pathogenesis of some of these morbidities (13, 14). pPROM before 34 weeks of gestation is usually managed conservatively, but as soon as intrauterine infection is diagnosed pregnancy has to be terminated to avoid these complications. The traditional methods of clinical diagnosis of intrauterine infections such as fever, uterine tenderness and fetal tachycardia lack specicity and may appear too late, while tests such as white blood count (WBC), erythrocyte sedimentation rate and C-reactive proteins lack both sensitivity and negative predictive value (15). Reliable methods for the diagnosis of early or asymptomatic infection are therefore needed. Amniocentesis carried out in women with preterm labor and pPROM has conrmed a rise in the concentration of proinammatory cytokines in the amniotic uid in cases where organisms were isolated or where there was evidence of histological chorioamnionitis (1618). A less invasive and more practical procedure is the measurement of these cytokines in maternal serum. If infection is the predominant cause of preterm labor and pPROM then proinammatory cytokine concentrations would be expected to be higher in these conditions compared to healthy patients not in labor. In the present study maternal serum IL-8, IL-6, TNF-a and interferon gamma (IFN-g) were measured in women in preterm, women in term labor and healthy preterm women not in labor to nd out whether there were differences in the concentrations of these cytokines in these groups. Serum levels were also compared in women in preterm labor with and without rupture of the membranes and between the mothers of newborns with positive bacterial culture and negative culture.
Patients and methods

Patients The study took place in the maternity hospital in the 6-month period from February 2000 to June 2000 after approval by the hospital ethics committee. Women enrolled in the study were divided into three groups: Group 1 consisted of women at 2436 weeks of gestation who were admitted to the hospital in preterm labor and were enrolled consecutively (n 77). Groups 2 and 3 acted as controls. Group 2 consisted of healthy women at
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Maternal serum cytokines in preterm labor investigated. Swabs were taken from the umbilical stump, nasopharynx, throat, rectum and gastric aspirates, as well as blood and urine culture. Infection was suspected when the newborn developed one or more of the following symptoms or signs: apnea, tachypnea, feeding intolerance, distention, vomiting, lethargy, temperature instability, hypotension, early onset jaundice, leukocytosis, leukopenia or thrombocytopenia. Cytokine measurements IL-6. The level of IL-6 in patients samples was measured using a Douset enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Minneapolis, MN, USA). The microtiter plates (Nunc, Maxisorb, Denmark) were coated with 100 mL of mouse anti-human IL-6 (2 mg/mL in phosphate-buffered saline, PBS) and incubated overnight at room temperature. The wells were washed three times and blocked with 300 mL of blocking buffer [1% bovine serum albumin (BSA), 5% sucrose in PBS with 0.05% NaN3]. The plates were washed three times and 100 mL of patients serum samples and standards were added and incubated for 2 h at room temperature. After that the plates were washed three times and 100 mL of biotinylated goat antihuman IL-6 (200 ng/mL) was added to all wells and incubated for 2 h at room temperature. At the end of the incubation period the plates were washed and 100 mL of streptavidinhorseradish peroxidase (HRP) (diluted 1 : 200) was added and incubated for 20 min at room temperature. After washing the plates, 100 mL of the substrate solution mixture (1 : 1 mixture of H2O2 and tetramethylbenzidine) was added to all wells for 20 min at room temperature. The reaction was stopped by the addition of 50 mL of stop solution (2NH2SO4) and the optical densities were read at 450 nm and corrected at 620 nm using a microplate reader (ICN, Titertek Multiscan MCC-340, Finland). The IL-6 concentrations were calculated in pg/mL from a standard curve using computer software. The sensitivity of the ELISA test for IL-6 was 0.055 pg/mL. IL-8. The levels of IL-8 in serum samples were determined using commercial Douset ELISA kits (R&D Systems) The same procedure used for the determination of IL-6 was used, but the plates were coated with 100 mL of mouse anti-human IL-8 (4 mg/mL) and the detection antibody was biotinylated goat anti-human IL-8 (20 ng/mL). The sensitivity of the Douset ELISA test for IL-8 was 4.64 pg/mL.

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TNF-. The levels of human TNF-a in serum samples were determined using commercial Douset ELISA kits (R&D Systems). The same procedure used for the determination of IL-6 was used, but the plates were coated with 100 mL of mouse anti-human TNF-a (4 mg/mL in PBS, pH 7.3) and detection antibody was rabbit anti-human TNF-a biotinylated antibody (300 ng/mL). The sensitivity of the Douset ELISA test for TNF-a was 0.103 pg/mL. IFN- . The levels of IFN-g in serum samples were determined using commercial Douset ELISA kits (R&D Systems). The same procedure used for the determination of IL-6 was used but the plates were coated with 100 mL of mouse antihuman IFN-g (4 mg/mL) and the detection antibody was biotinylated goat anti-human IFN-g (20 ng/mL) in reagent diluent containing 2% heat-inactivated normal goat serum. The sensitivity of the Douset ELISA test for IFN-g was 0.14 pg/mL. Statistics Because the cytokines concentrations were not normally distributed, the results were log transformed to normal distribution and statistical comparisons were carried out using analysis of variance or Students t-test when appropriate. The MannWhitney U-test was used for the comparison of demographic characteristics. Comparisons between proportions were performed with w2- or Fishers exact tests. Pearson correlation matrix was used to test for the correlation between the different cytokines. p < 0.05 was considered statistically signicant.
Results

The age and parity were similar between the groups (Table I). At admission 56 (72.7%) women from the preterm labor group and 16 (84.2%) women from the term labor group were in early labor (cervical dilatation 2 cm). Only three (3.9%) women from the preterm labor group and one (5.3%) woman from the term labor group were in advanced labor (cervical dilation ! 5 cm). The rest of the women had cervical dilations of 34 cm. Forty-one (53%) of the women in preterm labor delivered within 24 h of admission, 22 (28.6%) delivered within 48 h of admission, seven (9%) delivered after 48 h but within 7 days of admission, and six (7.8%) within 2 weeks of admission. All women in term labor delivered
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Table I. Demographic characteristics Preterm labor (n 77) 28 (1545) 33 (2436) 30 (39) 47 (61) Term labor (n 19) 24 (1940) 40 (3741) 6 (31.6) 13 (68.4) Preterm not in labor (n 47) 26 (1840) 33 (2636) 16 (34) 31 (66)

Characteristic Age (years), median (range) Gestational age (weeks), median (range) Parity Nulliparous no. (%) Multiparous no. (%)

No difference between groups in age. No difference in gestational age between preterm labor and preterm not in labor (MannWhitney U-test). No difference between groups in parity (w2-test).

within 24 h of admission. All the preterm women not in labor group delivered after 38 weeks of gestation. Thirteen (16.9%) women from the preterm labor group and five (10.6%) women from the preterm not in labor group were delivered by caesarean section. All women in the full-term labor group delivered vaginally. Sixty-six (85.7%) of the newborns that were delivered prematurely were admitted to the NICU. Twenty-six of them (39.4%) were suspected clinically as having infection and were bacteriologically investigated. The cultures were taken in the first 24 h following delivery. Immediately after the cultures were taken all received wide-spectrum antibiotic combinations of ampicillin and gentamycin or ampicillin and amikacin until the results of the culture were received. Bacteria were isolated from 17 (65.4%) newborns from different sites and in seven of them the blood culture was positive. Klebsiella was isolated from 10 babies, Escherichia coli from five babies, Staphylococcus aureus from three babies and Enterococci from one baby. Two babies died of Klebsiella septicemia. No significant differences were observed between newborns with positive culture and those with negative culture in the rate of antibiotics received by the mothers [16/ 17 (94.1%) vs. 6/9 (66.6%)] or delivery by caesarean section [7/17 (41%) vs. 3/9 (33.3%)]; but there was difference in the rate of pPROM [16/ 17 (94.1%) vs. 5/9 (55.5%); p 0.0344, Fishers exact test]. Three newborns from those with positive culture also had leukocytosis and positive C-reactive proteins, two had leukocytosis only, one had leukopenia and one had thrombocytopenia.

Only one newborn from the culture negative group had leukocytosis; the others had normal results. Five babies from the preterm not in labor group were admitted to the NICU for observation following delivery by caesarean section for different indications. All of them were discharged within 48 h in good condition. No baby from the full-term labor group was admitted to the NICU. There was no neonatal morbidity or mortality in the control groups. IL-8 was detectable in all women studied. IL-6 was detected in 69 (89.6%) women in preterm labor, in all women in term labor (100%) and in 43 (91.5%) preterm women not in labor. TNF-a was detected in 64 (83.1%) women in preterm labor, in 14 (73.7%) women in term labor and in 34 (72.3%) preterm women not in labor. IFN-g was detected in only seven (10%) women in preterm labor, in five (26.3%) women in term labor and in four (8.7%) preterm women not in labor. Because the number of women with detectable IFN-g was very small to give any meaningful comparison, no further analysis was carried out for this cytokine. There was no statistical difference in the concentration of all the cytokines between the groups (Table II), and no difference in the concentrations of any of the cytokines measured when women in preterm labor with ruptured membranes (n 63) were compared with those with intact membranes (n 14) (Table III). Of the women with ruptured membranes 39/63 (62%) had pPROM. No significant difference was found in the concentration of all cytokines in the maternal serum of the mothers of the newborn in whom organisms were isolated

Table II. Concentration of the cytokines in the groups Cytokine (pg/mL) log IL-8 (mean SD) log IL-6 (mean SD) log TNF-a(mean SD) Preterm labor (n 77) 3.42 1.56 1.87 1.44 2.28 1.72 Term labor (n 19) 3.78 1.63 1.55 1.06 2.06 1.66 Preterm not in labor (n 47) 3.89 1.62 1.72 1.64 2.32 2.10

p-value* 0.258 0.669 0.871

*Analysis of variance; no difference between groups.

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Table III. Cytokine concentrations in women in preterm labor according to the membranes status Cytokine (pg/mL) PTL with ruptured PTL with intact membranes(n 63) membranes (n 14) p-value* 2.90 0.91 1.88 1.16 2.43 1.73 0.055 0.952 0.720

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log IL-8 (mean SD) 3.54 1.65 log IL-6 (mean SD) 1.86 1.51 log TNF-a(mean SD) 2.25 1.70

PTL, preterm labor; *Students t-test; no difference between groups.

when compared to those in whom no organism was isolated. (Table IV). In all samples tested a significant correlation was found between the concentrations of IL-6 and IL-8 (Y 2.583 0.586X, p < 0.000), between IL-6 and TNF-a (Y 0.485 0.570X, p < 0.000) and IL-8 and TNF-a (Y 3.155 0.207X, p 0.004). No correlation was found between the concentration of IFN-g and the other cytokines.
Discussion

The purpose of the present study was to find out if preterm labor was associated with some proinflammatory cytokines and if these in turn can be indicators of underlying infection. There was no statistically significant difference in maternal serum cytokine concentrations measured between women in preterm labor compared to preterm women not in labor and women in term labor. This is in agreement with the study of Alvarezde-la-Rosa et al. (19) who found no significant difference in the serum concentrations of IL-6 and IL-8 between women in preterm labor and a control of preterm women not in labor. However, in similar studies Murtha et al. (20) reported elevation in the concentration of IL-6 in patients in preterm labor and von Minckwitz et al. (21) reported elevation in the concentrations of IL-6 and IL-8 but not in the concentration of TNF-a. The incidence of chorioamnionitis and intrauterine infection had been reported to be higher in patients with preterm labor with ruptured membranes compared to patients with intact membranes (22); and therefore theoretically one expects higher concentrations of cytokines in

Table IV. Cytokine concentrations in maternal serum of babies with positive and negative bacterial culture Cytokine (pg/mL) log IL-8 (mean SD) log IL-6 (mean SD) log TNF-a(mean SD) Positive bacterial culture (n 17) 3.23 1.4 1.85 1.4 2.96 1.82 Negative bacterial culture (n 9) 3.06 1.4 1.75 1.1 2.61 1.68

p-value* 0.776 0.861 0.634

*Students t-test; no difference between groups.

patients with ruptured membranes. However, in this study no difference was found in the maternal serum cytokine concentration between women with ruptured membranes and those with intact membranes. We hypothesized that infection may be the major cause of preterm labor and pPROM. Although we did not look for direct evidence of intrauterine infection and the number of newborns who were bacteriologically investigated was small, which are limitations of this study, positive bacterial culture in 17/ 26 (65.4%) of the neonates who were bacteriologically investigated may indirectly indicate that there was intrauterine infection in at least some of the cases in this group. As all cultures were done in the first day following delivery it was unlikely that the organisms isolated were of NICU nosocomial infection origin. NICU nosocomial infections rarely develop in the first 24 h (23). Vaginal colonization might have occurred in only some of the 10/17 (58.8%) neonates who were delivered vaginally. However, we did not find significant differences in the concentrations of cytokines between women whose babies had positive culture and those with negative culture. This throws doubt on the usefulness of the measurement of these cytokines in the maternal serum for the diagnosis of subclinical fetal infections. This is in variance with the study of Pfeiffer et al. (24), who reported a significant correlation between a rise in IL-6 in maternal serum and the onset of neonatal infection in patients with PROM. Studies comparing maternal serum concentrations of IL-6 in women in preterm labor with histologic evidence of chorioamnionitis with those without chorioamnionitis found no significant differences in the maternal serum concentrations of IL-6 although their concentrations in the amniotic fluid or umbilical cord blood were significantly higher in women with chorioamnionitis (25, 26). These studies point out that the maternal compartment differs from the fetal compartment and the inflammatory responses in the fetal compartment are not necessarily reflected in maternal serum. On the other hand, Maeda et al. (27) reported high maternal serum concentration of IL-6 in women with proven histologic chorioamnionitis compared to women with no chorioamnionitis, but found no difference in the concentration of IL-8, while Shimoya et al. (28) reported elevated concentrations of IL-8 but no increase in the concentration of IL-6. In our study we found a positive correlation between the concentrations of IL-6, IL-8 and TNF-a, in that when there is a rise in one there will also be a rise in the others. This positive correlation has also been reported previously (19, 29).
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References
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It had been reported that IL-6 and IL-8 levels are increased by the process of labor even without the presence of infection, and that the increase in the maternal serum concentrations of cytokines correlates with the strength of uterine contractions and the advancement in labor (29, 30). In this study we could not find any differences between women in labor at term or preterm and preterm women not in labor. However, most of our patients were in early labor when blood was withdrawn from them (72.7% and 84.2% in preterm and term labor, respectively). Olah et al. (31), comparing laboring and nonlaboring women at term, found increased levels of IL6, IL-8 and IFN-g in the amniotic fluid of women in labor with a positive correlation between the levels of IL-6 and IFN-g, but the maternal sera showed only an increase in IL-8.The levels of IL-6 and IFN-g were below the limits of detection. This is at variance with the study of Veith and Rice (32), who reported absence of IFN-g in the amniotic fluid but detectable levels in 34% of serum samples tested. However, they detected IFN-g in all gestational tissue examined (placenta, amnion and choriodecidua). In our study serum IFN-g was detected in only a small number of women, which precludes statistical analysis. In addition, we could not find any correlation between IFN-g and the other cytokines measured. IFN-g is a type 1 cytokine while the others are type 2 cytokines and therefore they may have different roles to play in this context. Further studies to elucidate the place of this cytokine in pregnancy and labor are needed. The variation between different studies whether of women in labor or pPROM with or without evidence of infection may be explained by the differences in assay methods or differences in the sensitivity of different kits. It should also be noted that the amount of proinflammatory cytokines entering the maternal circulation from the feto-placental unit at the outset of the infection or latent phase of labor is very small so that differences might be undetectable. However, with florid infection and maternal leukocytosis, which also occurs during labor, there may be an increase in the levels of maternal serum cytokines due to an additional separate maternal compartment response, the white cells themselves being a source of cytokines production. So far the studies reported in the literature on the measurements of cytokines in maternal sera in preterm labor are few and have consisted of small numbers of patients. More studies in maternal sera are needed with standardization of assay methods in larger sample sizes before a definite conclusion can be reached.
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preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995; 172: 96070. Alvarez-de-la-Rosa M, Rebollo FJ, Codoceo R, Gonzalez GA. Maternal serum interleukin 1, 2, 6, 8 and interleukin-2 receptor levels in preterm labor and delivery. Eur J Obstet Gynecol Reprod Biol 2000; 88: 5760. Murtha AP, Greig PC, Jimmerson CE, Herbert WN. Maternal serum interleukin-6 concentration as a marker for impending preterm delivery. Obstet Gynecol 1998; 91: 1614. von Minckwitz G, Grischke E, Schwab S, Hettinger S, Loibl S, Aulmann M et al. Predictive value of serum interleukin-6 and -8 levels in preterm labor or rupture of the membranes. Acta Obstet Gynecol Scand 2000; 79: 66772. Seo K, McGregor JA, French JI. Preterm birth is associated with increased risk of maternal and neonatal infection. Obstet Gynecol 1992; 79: 7580. Sastre CJBL, Cotallo DC, Colomer BF, Grupo de Hospitales Castrillo. Neonatal sepsis of nosocomial origin: an epidemiological study from the Grupo de Hospitales Castrillo. J Perinat Med 2002; 30: 14957. Pfeiffer KA, Reinsberg J, Rahmun A, Schmolling J, Krebs D. Clinical application of maternal serum cytokine determination in premature rupture of membranes interleukin-6, an early predictor of neonatal infection? Acta Obstet Gynecol Scand 1999; 78: 7748. Lencki S, Maciulla M, Eglinton G. Maternal and umbilical cord serum interleukin levels in preterm labor with clinical chorioamnionitis. Am J Obstet Gynecol 1994; 170: 134551. Salafia CM, Sherer DM, Spong CY, Lencki S, Eglinton GS, Parkash V et al. Fetal but not maternal serum cytokine levels correlate with histologic acute placental inflammation. Am J Perinat 1997; 14: 41922.

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27. Maeda K, Matsuzaki N, Fuke S, Mitsuda N, Shimoya K, Nakayama M et al. Value of the maternal interleukin 6 level for determination of histologic chorioamnionitis in preterm delivery. Gynecol Obstet Invest 1997; 43: 22531. 28. Shimoya K, Matsuzaki N, Taniguchi T, Okada T, Saji F, Murata Y. Interleukin-8 level in maternal serum as a marker for screening of histological chorioamnionitis at term. Int J Gynaecol Obstet 1997; 57: 1539. 29. Hebisch G, Grauaug AA, Neumaiier-Wagner PM, Stallmach T, Huch A, Huch R. The relationship between cervical dilatation, interleukin-6 and interleukin-8 during term labor. Acta Obstet Gynecol Scand 2001; 80: 8408. 30. Arntzen KJ, Lien E, Austgulen R. Maternal serum levels of interleukin-6 and clinical characteristics of normal delivery at term. Acta Obstet Gynecol Scand 1997; 76: 5560. 31. Olah KS, Vince GS, Neilson JP, Deniz G, Johnson PM. Interleukin-6, interferon-gamma, interleukin-8, and granulocyte-macrophage colony stimulating factor levels in human amniotic fluid at term. J Reprod Immunol 1996; 32: 8998. 32. Veith GL, Rice GE. Interferon gamma expression during human pregnancy and in association with labour. Gynecol Obstet Invest 1999; 48: 1637.

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Address for correspondence: Ahmad M. Bahar PO Box 641 College of Medicine Abha Saudi Arabia e-mail: abahar2@hotmail.com

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