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complete and partial moles and in nonmolar abortuses. AMj 0BSTET GYNECOL 1984;149:129.

5. Szulman AE, Surti V. The syndromes of hydatidiform mole. II. Morphologic evolution of the complete and par­tial mole. AM J 0BSTET GYNECOL 1978; 132:20.

6. Ma HK, Wong LC. Gestational trophoblastic disease in Hong Kong. Semin Oncol 1982;9:224.

7. Korenman SG, Stevens RH , Carpenter LA, Robb M, Niswender GD, Sherman BM. Oestradiol radioimmuno­assay without chromatography: procedure, validation and normal values. J Clin Endocrinol Metab 1974;38:718.

8. Koligian KB, Stormshak F. Nuclear and cytoplasmic es­trogen receptors in ovine endometrium during the es­trous cycle. Endocrinology 1977; I 01:524.

9. Vaitukaitis J, Braunstein GD, Ross GT. A radioimmuno­assay which specifically measures human chorionic go­nadotropin in the presence of human luteinizing hor­mone. AM j 0BSTET GYNECOL 1972; 113:75 1.

10. Miyake A, Aono T, Tanizawa 0, Kurachi H, Kurachi K. Restoration of the gonadotrophin response to LH-RH and oestrogen administration in patients after molar abor­tion. Acta Endocrinol 1975;9 1:30.

II. Miyake A, Aono T, Kurachi H, Tsutsumi H, Kurachi K. Restoration of the ovarian response to gonadotropins in patients after molar abortion. Obstet Gynecol 1981 ;58: 566.

12. Dawood MY, Ratnam SS, Teoh ES. Serum estradiol-17[3 and serum human chorionic gonadotropin in patients with hydatidiform moles. AM j 0BSTET GYNECOL 1974; 119:904.

13. Goldstein DP, Berkowitz RS. The diagnosis and manage­ment of molar pregnancy. In: Goldstein DP, Berkowitz RS, eds. Gestational trophoblastic neoplasms. Philadel­phia: WB Saunders, 1982: 143.

The association of subclinical infection with preterm labor: The role of C-reactive protein

Ronald K. Potkul, M.D., Atef H. Moawad, M.D., and Kathryn L. Ponto, B.A.

Chicago, Illinois

The role of subclinical intrauterine infection in preterm labor was evaluated prospectively in 40 patients and appropriate control subjects. The 24 preterm labor patients (60%) with a negative C-reactive protein value responded to tocolysis 95.8% of the time, with a mean delay of delivery of 35.5 days and a mean gestational age of 36.9 weeks. The 16 patients (40%) with a positive C-reactive protein value responded to tbcolysis only 37.5% of the time, with a mean delay of delivery of 14.4 days and a mean gestational age of 33.2 weeks. Pathologic evidence of chorioamnionitis was present in 32.9% of 310 preterm deliveries as compared to only 22.3% of 1631 term deliveries. The presence of subclinical infection must be considered in cases of preterm labor, especially among patients for whom tocolytic therapy is unsuccessful. (AM J 0BSTET GYNECOL 1985;153:642-5.)

Key words: C-reactive protein , preterm labor, subclinical infection

Despite the fact that it is the largest cause of perinatal morbidity and mortality, the cause of preterm delivery is poorly understood. Recently, several reports have suggested that a percentage of premature labor cases may be caused by subclinical chorioamnionitis and that, in addition, this type of infection may affect the uterine response to tocolysis. ,_,

There are a number of indications that subclinical infections contribute to preterm labor. Bobitt et al.," in 1981 , isolated microorganisms from amniocentesis specimens of patients in preterm labor; the membranes

From the Department ofObstetrics and G_vnecology and The Perinatal Center, The Pritzker School of Medicine and The Chicago Lying­In Hospital, The University of Chicago.

Supported in part b_v the Mother's Aid Research Fund, The Chicago Lying-In Hospital.

Received for publication February 22, 1985; revised and accepted August 26, 1985.

Reprint requests: Atef H. Moawad, M.D. , The Chicago Lying-In Hospital, 5841 South Maryland Ave., Chicago, IL 60637.

were intact in 25% of these cases. The significance of this finding is not clear since microorganisms can also be found in 10% of patients in normal term labor.' A study by Miller et al.' indicates that premature labor and delivery may frequently reflect undiagnosed sub­clinical intrauterine infection.

C-reactive protein is a serum globulin that forms a precipitate with the C-fraction carbohydrate of strep­tococcal pneumonia; it is frequently elevated in cases of bacterial infection and tissue injury and recovery. The purpose of this study was to examine the role of subclinical chorioamnionitis in premature labor and evaluate the use of C-reactive protein as a possible marker for this type of infection.

Material and methods

The first phase of the study consisted of the micro­scopic examination of placentas for evidence of cho­rioamnionitis. All of the I63 I deliveries between Feb­

642

C-reactive protein in preterm labor 643Volume 153 Number 6

Table I. Comparison of groups

Age (y1) Gmvidity Parity Abo1·tions Gestational age (wk)

Group N Mean I SE Mean I SE Mean I SE Mean I SE M ean I SE

Preterm control 10 23.6 1.8 3.30 0.62 1.50 0.48 0.80 0.33 30.9 0.9 Term control 12 22.7 0.9 2.42 0.23 1.00 0.42 0. 15 39.2 0.4

0.21 Negative C-reactive 24 23.8 1.3 2.71 0.38 1.33 0.38 0.16 31.9 0.5

protein 0.33 Positive C-reactive 16 23.1 1.0 2.80 0.32 1.32 0.50 0. 16 31.2 0.5

protein 0.29

Table II. C-reactive protein values correlated with groups

Negative C-reactive Positive C-reactive protein ( ,;;;0.7 mgldl) protein (> 0.7 mgldl)

Group N n l Preterm control 10 10

Preterm labor 40 24

Term labor control 12 II

ruary 1, 1983, and October 31, 1983, in which labor was neither induced nor complicated by premature rupture of the membranes(> 12 hours), were included. Pathologic evidence of chorioamnionitis was defined as: (1) infiltration of the extraplacental membranes by polymorphonuclear leukocytes, (2) accumulation of polymorphonuclear leukocytes in the intervillous space immediately below the chorionic plate, (3) infiltration of the chorionic plate by leukocytes, and (4) angiitis of the umbilical vessels. The number of cases with patho­logic evidence of chorioamnionitis was compared for both term (;.37 weeks) and preterm (< 37 weeks) births by means of the x~ test for statistical significance.

Fifty patients with singleton pregnancies who were found to be in premature labor were enrolled in the second phase of the study after meeting several criteria. Each patient was required : (l) to be between 24 and 36 weeks' gestation; (2) to have intact membranes; (3) to be undergoing uterine contractions every 5 minutes for at least 1 hour, which were unresponsive to intra­venous hydration; (4) to have a cervix judged favorable for tocolysis; (5) to manifest no evidence of fetal dis­tress; (6) to be receiving no tocolytic drugs; (7) to have no evidence of present or recent clinical infection.

A specimen of urine for culture was obtained from all patients at the time of admission in order to detect any current urinary tract infection. Of the 50 patients enrolled in the study, 10 were excluded for failure to meet the above requirements. These 10 cases included one twin gestation, two patients already receiving rito­drine, one with a gestational age of < 24 weeks, one with a gestational age of > 37 weeks, two receiving am­picillin for a recent urinary tract infection , two with urine cultures demonstrating the presence of> 10" bac­

% 11 l % p

100

60

91.7

0

16

0

40

8.3

< 0.05

< 0.05

teria, and one patient with a fever of unknown origin. The control groups consisted of ( 1) 10 patients between 24 and 36 weeks' gestation who were not in labor and (2) 12 patients in labor at term with intact membranes.

Blood for a quantitative C-reactive protein assay (a nephelometric assay with the Beckman Immunochem­istry Analyzer) was obtained from the study group and the two control groups as part of the patient's routine admission laboratory tests .. The preterm patients were treated with intravenous ritodrine according to a stan­dard obstetrics protocol by the obstetrics staff. Each case was managed without knowledge of the C-reactive protein results. Tocolytic therapy was abandoned if spontaneous rupture of the amniotic membranes oc­curred or if advanced cervical dilatation and efface­ment were encountered. Following delivery the pla­centa was examined microscopically for evidence of chorioamnionitis. The C-reactive protein levels of the preterm labor patients were then compared to those of the control groups for both the numbers with patho­logic evidence of chorioamnionitis and the degree to

which gestation was prolonged by tocolysis . Statistical analysis was performed with Student's t test and the x~

test; results were considered statistically significant if the confidence interval (p) was <0.05.

Results

Three hundred sixty-three (22.3%) of the 1631 term deliveries showed pathologic evidence of chorioam­nionitis as compared to 102 (32.9%) of the 3 10 preterm deliveries during the 9-momh study period. This dif­ference is statistically significant (p < 0.05).

There was no significant difference in demographic characteristics (age, gravidity, parity, number of abor­

644 Potkul, Moawad, and Ponto November 15, 1985 Am J Obstet Gynecol

Table III. Correlation between C-reactive protein and pathologic evidence of chorioamnionitis

Negative C-reactive protein Positive C-reative protein

Chorioamnionitis No chorioamnionitis Chorioamnionitis No chorioamnionitis

Group

Preterm labor Term labor control Total

N

38* 12 50

n

4 3 7

I %

18.2

21.2

n

18 8

26

I %

81.8

78.8

n

10 0

10

I %

62.5

58.8

n

6 I

7

I %

37.5

41.2

p

<0.01 NS

<0.01

*Pathology reports were not available in two patients.

Table IV. C-reactive protein correlated with prolongation of gestation

Days to delivery Gestational age at delivery ( wk)

C-reactive protein N Mean SE Mean SEI 1 Negative 24 35.5 4.1 36.9 0.6 Positive 16 14.4 5.0 33.2 0.7 p < 0.01 < 0.01

Table V. C-reactive protein correlated with results of tocolysis

Successful Failed Term birth Preterm birth

C-reactive protein N n I % n I % n 1 % n 1 %

Negative 24 23 95.8 I 4.2 13 54.2 II 45.8 Positive 16 6 37.5 10 62.5 2 12.5 14 87.5 p < 0.001 < 0.01

tions, and gestational age) between the study and the mean gestational age at delivery were 35.5 days and control group patients (Table I) . 36.9 weeks for the group with negative C-reactive pro­

In an attempt to apply the C-reactive protein assay tein versus 14.4 days and 33.2 weeks for the group with as a highly sensitive but somewhat less specific clinical positive C-reactive protein (Table IV). test, levels of >0.7 were considered positive for the Tocolysis was successful in prolonging gestation for remainder of the analysis. With the use of this value 1 week in 23 of the 24 patients (95.8%) witha negative the C-reactive protein assay was found to be positive C-reactive protein value (Table V) . The single failure for 40% of the preterm labor group. There were no occurred in a patient who required discontinuation of cases with positive C-reactive protein assays among pre­ ritodrine therapy at 30.5 weeks because of severe ma­term patients who were not in labor and only an 8% ternal tachycardia. The contractions, which had ceased incidence among term patients in labor (Table II). The during ritodrine therapy, recurred after termination of differences between the preterm labor group and each the drug. Gestation was prolonged for > 7 days for only of the two control groups were significant. six of the 16 patients (37 .5%) with a positive C-reactive

The C-reactive protein test results were found to cor­ protein assay. Gestation was prolonged to term (~37 respond reasonably well with the microscopic diagnosis weeks) in 54.2% of the patients with a negative e-re­of chorioamnionitis, which was present in 62.5% of active protein value. The same was true for only 12.5% those patients with a positive C-reactive protein assay of the patients with positive C-reactive protein values. (Table III). None of these patients exhibited any of the

Commentclinical signs of chorioamnionitis. In two of the pa­tients with negative results for both the pathologic and The results of this study point to subclinical cho­C-reactive protein tests and in three patients with pos­ rioamniotic infection as a contributing factor in the itive results in both cases, the membranes had ruptured cause of preterm labor. more than 12 hours before delivery. C-reactive protein was evaluated as a possible marker

Tocolysis was significantly more successful in the for subclinical chorioamnionitis because of past evi­group of patients with negative C-reactive protein assay dence indicating that the C-reactive protein test is more results. The mean number of days to delivery and the sensitive than the appearance of fever, leukocytosis,

Volume 153 Number 6

or fetal tachycardia in predicting the presence of in­fection.6· 7

The level of C-reactive protein that was considered abnormal in this study was >0.7 mg/dl. This is in con­trast to the cutoff point of 2 mg/dl chosen in two pre­vious studies dealing with premature rupture of the membranes from our institution.6

· 7 The 2 mg/dl level

was arbitrarily chosen in an attempt to apply the C­reactive protein assay as a highly specific but somewhat less sensitive clinical test of pending clinical infectious morbidity. This was necessary since decisions concern­ing induction of labor are based largely on C-reactive protein levels.

The 0.7 mg/dllevel chosen in this study was an at­tempt to apply the C-reactive protein assay as a highly sensitive but somewhat less specific indicator of sub­clinical infection rather than infectious morbidity.

Quality control of the Beckman Automated Immu­nochemistry system by the company and The Univer­sity of Chicago Serology laboratory has confirmed that the C-reactive protein level is <0.6 mg/dl in a normal population.

Several aspects of these results are noteworthy. Al­though the number of cases is limited, we have shown that normal pregnancy and normal term labor do not raise C-reactive protein levels significantly. It is inter­esting to note that 8% of the patients in labor at term had elevated C-reactive protein levels, a figure that ap­proximates the 10% incidence of the presence of mi­croorganisms in amniotic fluid obtained from patients in labor at term.' In contrast, 40% of our preterm labor study group had elevated C-reactive protein values . The histologic examination of placentas from preterm deliveries at our institution revealed that chorioam­nionitis was present 32.9% of the time. Again, the in­cidences of elevated C-reactive protein and histologic chorioamnionitis are fairly similar. It seems reasonable to argue that, in the absence of clinical infection of the urogenital or other systems, subclinical infection plays an etiologic role in the onset of preterm labor in ap­proximately one third of preterm labor patients.

We were also able to demonstrate that when the C­reactive protein assay was negative, ritodrine therapy

C-reactive protein in preterm labor 645

was successful in virtually every case in which the drug was well tolerated . A recent study by Handwerker et al.8 has also examined the success rate of tocolysis with respect to C-reactive protein levels. Their lower success rate may be due to the inclusion of cases of urinary tract infection.

Our results indicate that it may become possible to predict the success or failure of tocolytic therapy on the basis of the results of the assay for C-reactive pro­tein. We recommend, in cases of preterm labor with high C-reactive protein levels or in cases where 13-sym­pathomimetic agents fail to stop preterm uterine con­tractions, that the presence of infection as a contrib­uting factor should be suspected, even in the absence of any clinical manifestation of the infectious process.

The task of the prospective identification of causative agents, although a tedious and difficult one, is clearly called for when one considers that in our population approximately one third of cases of preterm labor may have an infectious cause.

REFERENCES I. Bobitt JR, Ledger WJ. Unrecognized amnionitis and pre­

maturity: a preliminary report.] Reprod Med 1977;19:1. 2. Bobitt JR, Ledger WJ. Amniotic fluid analysis. Its role in

maternal and neonatal infection. Obstet Gynecol 1978; 51:56.

3. BobittJR, Hayslip CC, DamatoJD. Amniotic fluid infection as determined by transabdominal amniocentesis in patients with intact membranes in premature labor. AM J OBSTET GYNECOL 1981;140:947.

4. Miller JM, Pupkin MJ, Hill GB. Bacterial colonization of amniotic fluid from intact fetal membranes. AMJ OBSTET GYNECOL 1980; 136:796.

5. Lis twa HM, Dobek AS, CarpenterJ, et al. The predictability of intrauterine infection by analysis of amniotic fluid. Ob­stet Gynecol 1976;48:31.

6. Ismail MA, Zinaman MJ, Lowensohn R, Moawad AH. The significance of C-reactive protein levels in women with pre­mature rupture of membranes. AM J OBSTET GYNECOL 1985; 151 :541.

7. Evans MI , Hajj SN, Devoe LD, Angerman NS, Moawad AH. C-reactive protein as a predictor of infectious mor­bidity with premature rupture of membranes. AMJ OBSTET GYNECOL 1980; 138:648.

8. Handwerker SM, Nergesh AT, Verma UL, et al. Correla­tion of maternal serum C-reactive protein with outcome of tocolysis. Obstet Gynecol 1984;63:220.