Biophysical profile in predicting acute ascending infection in preterm rupture of membranes before 32 weeks

Biophysical Profile in Predicting Acute Ascending Infection in Preterm Rupture of Membranes Before 32 Weeks ALESSANDRO GHIDINI, MD, CAROLYN M. SALAFIA, MD, VALENTINA KIRN, MD, VALENTINA DORIA, MD, AND CATHERINE Y. SPONG, MD Objective: To assess the performance of the biophysical profile (BPP) and its components within 24 hours of delivery in predicting histopathologic evidence of severe acute placental inflammation in women with premature rupture of membranes (PROM) before 32 weeks’ gestation. Methods: We examined placentas from a series of consecutive, nonanomalous, live-born, singleton infants delivered before 32 weeks’ gestation after PROM. In 166 cases, biophysical profiles (BPP) were done within 24 hours of birth. Histologic evidence of acute inflammation was assessed in the maternal (amnion) and fetal (chorionic and umbilical cord vessels) compartments, and scored on a severity scale of 0 – 4 by a single pathologist masked to clinical data. The presence and severity of acute inflammation was related to BPP results and its individual components. Results: The overall prevalence of severe acute inflammation, ie, a score of 3 or 4, was 59% (98 of 166). In 30 (18%) cases it was present in the amnion, in 49 (30%) cases in chorionic or umbilical cord vessels, and in 19 (11%) cases in maternal and fetal compartments. There was no association between abnormal BPP score and presence or absence of severe acute placental inflammation (48% versus 46%, P ⴝ .7). Our study had a 90% power to detect a 0.26 difference between them. When rates of abnormal BPP scores were compared in cases with different degrees of acute inflammation in the maternal, fetal, or both compartments, no association was found. When the individual components of the BPP were analyzed in relation to site and severity of acute inflammation, no association was detected. Conclusion: We did not find evidence of a dose-response relationship between acute placental inflammation and BPP score or its individual components in cases of PROM with infants delivered before 32 weeks. Mediators other than infection might affect BPP in preterm PROM. (Obstet Gy-

From the Department of Obstetrics and Gynecology, Georgetown University Medical Center, Washington, DC; and Department of Pathology, Columbia Presbyterian Medical Center, New York, New York. Partial support for Dr Salafia was provided through an inter-agency personnel agreement with the National Institutes of Health.

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necol 2000;96:201– 6. © 2000 by The American College of Obstetricians and Gynecologists.)

The biophysical profile (BPP) test was originally developed to detect evidence of declining fetal well being during uteroplacental insufficiency. In premature rupture of membranes (PROM), the BPP has been used to diagnose subclinical intra-amniotic infection or impending neonatal infection.1 However, evidence supporting the BPP as a predictor of infections is lacking. Several studies have reported high predictive value of an abnormal score, and its individual components for diagnosing proven or suspected neonatal sepsis and microbiologic evidence of intra-amniotic infection in amniotic fluid (AF) collected by amniocentesis.1–5 Those investigators hypothesized that release of inflammatory mediators within the infected uterine cavity could be responsible for the changes in the fetal behavioral profile. One group also suggested that the changes in the fetal BPP mainly indicated fetal sepsis rather than maternal or intrauterine infection.6 Other investigators have been unable to replicate those findings and have questioned the clinical use of BPP for predicting perinatal infections.7–9 Several variables might account for the discrepant conclusions, including study populations that included different gestational ages; sample sizes that were often small; BPPs done at different intervals from delivery; and that documented neonatal sepsis is rare because aggressive intrapartum antibiotics can result in underdiagnosis of it. Histopathologic placental examination avoids some of those shortcomings because the findings are not influenced by antibiotics in the short course. Whereas clinical and laboratory infectious outcomes follow a dichotomous definition (a neonate is either infected or not; an AF culture is positive or not), acute inflamma-

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tion in placental tissues can be graded. That allows investigators to study whether a dose-response relationship exists between intrauterine infection and biophysical variables that would indicate a causal relationship. The purposes of our study were to assess whether BPP within 24 hours of delivery correlates with histopathology evidence of acute placental inflammation, the landmark of infection, and to establish whether alterations of BPP components reflect histologic evidence of a predominantly maternal or fetal acute inflammatory response to ascending infections.

Table 1. Criteria for Scoring Biophysical Variables Criterion Nonstress test (n accelerations per 20 minutes) Fetal movements (n per 30 minutes) Breathing movements (n seconds per 30 minutes) Fetal tone (n of flexions or extensions per 30 minutes) Amniotic fluid volume (cm) Placental grade

Score 2*

Score 1*

Score 0*

ⱖ5

2– 4

⬍2†

ⱖ3

1 or 2†

⬍1†

ⱖ60

ⱖ30

⬍30†

ⱖ2

1

ⱖ2 0 –2

1† Not evaluated

None† ⬍1† 3

* Score according to Vintzileos et al.1 Abnormal score according to Manning et al10 and subsequent modifications.11 †

Materials and Methods The study group consisted of consecutive women admitted between July 1988 and March 1994 for conservative treatment of PROM and who delivered before 32 weeks’ gestation. Diagnoses of membrane rupture were established by sterile speculum examination that found pooled fluid, ferning, and alkaline pH (nitrazine paper). Digital pelvic examinations were not done unless women were believed to be in active labor or a decision had been made to induce labor. We excluded women with multiple gestations, diabetes, chronic hypertension, or indications for elective preterm delivery, such as placenta previa, fetal growth restriction, or contraindications for expectant treatment, such as abruption, nonreassuring fetal heart tracing, fetal death, or clinical chorioamnionitis (defined by two or more of the following: maternal temperature above 37.8C, maternal tachycardia at least 120 beats per minute, white blood cell count at least 20,000/mm3 without prior corticosteroid administration, fetal tachycardia above 160 beats per minute, or uterine tenderness). On admission, maternal vital signs were recorded, and electronic fetal monitoring was used to detect signs of nonreassuring fetal heart rate tracing and document characteristics of uterine activity. Without labor, nonreassuring fetal heart rate tracing, or obvious signs of clinical infection, ultrasonographic examinations were done to assess gestational age and to determine BPP1 (General Electric 2600, Wilmington, MA). Table 1 shows the scoring system. The BPP was repeated daily. Patients were observed in the hospital and treated conservatively. Corticosteroid therapy (betamethasone 12 mg intramuscularly daily for 2 days) was administered to most women after initial evaluation. Temperatures were taken four times a day, and white blood cells were counted daily. Antibiotics were administered only after clamping the cord, unless the mother had positive cervicovaginal cultures for group B streptococcus or developed clinical chorioamnionitis. Indications for delivery included spontaneous labor, chorioamnionitis,

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abnormal fetal heart rate tracing, and persistently low BPP score (at most 7 of 12 on two examinations 2 hours apart in the presence of a nonreactive, nonstress test and in the absence of fetal breathing).1 Abnormal BPP scores and their individual components within 24 hours of delivery were correlated with histopathologic evidence of severe acute inflammation. For analysis of the diagnostic indices of individual BPP components, we adopted the more commonly used cut-offs proposed by Manning et al10,11 to define abnormal scores, including AF volume under 2 cm, fetal breathing movements under 30 seconds in 30 minutes, fetal movements up to two in 30 minutes, and nonstress test with fewer than two accelerations in 20 minutes. Placental grade has been shown to have no value in predicting infectious outcome.1 For pathologic examination of the placenta, we examined from each woman two sections of umbilical cord, a section of membranes from the site of rupture, a membrane roll extending from the area of membrane rupture to the placental margin, and at least one sample that measured at least 2.5– 4 cm in length taken from the central 60% of the chorionic plate with two chorionic vessels taken from an area with minimal subchorionic fibrin. Sections of tissue blocks were stained with hematoxylin-eosin and read by a single observer (C.M.S.). Histologic evidence of acute ascending inflammation in amnion, umbilical, and chorionic vessels was recorded and scored with a semiquantitative scale 0 – 4 as previously published.12 Severe acute inflammation was defined as a score of 3 or 4. Severe acute inflammation in the amnion was considered a marker of activation of the maternal immune system in response to ascending infection, whereas severe acute inflammation of umbilical cord or chorionic vessels was considered to indicate a response of the fetal immune system to ascending infection. Statistical analysis was done with StatView (Abacus

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Table 2. Demographic Characteristics

Variable Mean maternal age (years) ⫾ standard deviation Nulliparity Nonwhite race Gestational age at delivery (wk)

Maternal SAI (n ⫽ 30)

Fetal SAI (n ⫽ 49)

Maternal and fetal SAI (n ⫽ 19)

29.1 ⫾ 5.8

28.1 ⫾ 6.8

29.6 ⫾ 4.4

15 (50%) 16 (53%) 26.5 ⫾ 2.2

24 (49%) 17 (35%) 27.9 ⫾ 2.5

7 (37%) 7 (37%) 26.5 ⫾ 1.8

SAI ⫽ severe acute inflammation.

Concepts Inc., Berkeley, CA) and Epistat version 4.0 (Epistat Services, Richardson, TX). ␹2 and analysis of variance after log transformation were used as appropriate. Two-tailed P ⬍ .05 was considered statistically significant. Our study had a 90% power to detect a 0.26 difference between the proportions of an abnormal BPP score in the presence versus absence of severe acute inflammation (48% or 47 of 98, versus 46% or 31 of 68) with ␣ ⫽ 0.05 and ␤ ⫽ 0.80.

Results A total of 166 cases met study criteria. The mean ⫾ standard deviation (SD) maternal age was 27.9 ⫾ 6.3 years. Seventy women (42%) were nulliparas. The mean gestational age at PROM was 26.3 ⫾ 3 weeks (range 20 –32 weeks) and at delivery was 28.1 ⫾ 2.5 weeks (range 24 –32 weeks). Mean (⫾ SD) birth weight was 1171 ⫾ 372 g (range 480 –1950 g). A clinical diagnosis of chorioamnionitis was made in 62 women (37%). Neonatal sepsis was diagnosed in 32 infants (19%) and suspected in additional 81 infants (49%). There were nine early neonatal deaths (ie, within 48 hours of birth). The overall prevalence of histopathologic diagnoses of severe acute inflammation was 59% (98 of 166). In 30 cases, severe acute inflammation was in the amnion, in 49 in chorionic or umbilical cord vessels, and in 19 it was in the amnion and umbilical-chorionic vessels, indicating activation of maternal and fetal immune systems to ascending infection. Table 2 shows relevant demographic characteristics in relation to severe intrauterine infection. No difference was present among the groups. We then correlated the BPP obtained within 24 hours of delivery with histology indices of infectious pregnancy outcomes. An abnormal BPP score was present in 39% (78 of 166) of cases, and it was similarly prevalent in the presence or absence of severe acute inflammation (48%, 47 of 98 compared with 46%, 31 of 68, respectively, P ⫽ .7). Power analysis showed that 9775 cases would be required in each group (with versus without severe placental inflammation) to achieve statistical significance (␣ ⫽ .05, ␤ ⫽ .80). There

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Table 3. Relationship Between Biophysical Profile and Histopathologic Evidence of Maternal and Fetal Immunoresponse Histologic findings Maternal amnionitis Severe (grades 3– 4) Mild (grades 1–2) Absent Fetal vasculitis at umbilical and/or chorionic vessels Severe Mild (grades 1–2) Absent Maternal and fetal inflammation Severe (grades 3– 4) Mild (grade ⬍3) Absent

Biophysical profile ⱕ7 of 12

P

13 of 30 (43%) 17 of 44 (39%) 48 of 92 (52%)

.30

27 of 49 (55%) 20 of 41 (49%) 31 of 70 (44%)

.51

7 of 19 (37%) 44 of 84 (52%) 27 of 63 (43%)

.33

was no significant correlation between BPP score and gestational age (R2 ⫽ .007, P ⫽ .16). To assess whether BPP could differentiate a predominant maternal or fetal immunoresponse in cases of severe acute inflammation, and to establish a doseresponse relationship between intrauterine infection and BPP, we compared rates of abnormal BPP scores in cases with severe, mild, and absent acute inflammation in the mother (amnionitis), fetus (umbilical or chorionic vasculitis), or both mother and fetus (Table 3). The overall BPP score did not differentiate severity or site of acute intrauterine inflammation. When we examined individual biophysical components, none was associated with placental histologic indicators of worsening acute inflammation in maternal (Table 4) or fetal (Table 5) tissues. When we compared sensitivities and specificities of the individual BPP score components in predicting severe acute inflammation indicating either maternal or fetal immunoresponse (Table 6), none of the individual BPP variables was significantly associated with site of origin of acute inflammation. Some biophysical components, such as AF volume and nonstress test, showed better sensitivity, whereas others had better specificity, such as body movements and fetal tone.

Discussion We found that neither abnormal BPP score within 24 hours of delivery nor abnormal results of its individual components indicated histologic evidence of intrauterine infection. The lack of a statistically significant association between total BPP score and progressive severity of acute placental inflammation militates against a causal relationship between the two. This conclusion is at variance with those of other clinical studies that

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Table 4. Relationship Between Abnormal Biophysical Profile Components and Histopathologic Evidence of Acute Inflammation in Maternal Tissues Acute amnionitis

Abnormal biophysical profile parameter*

Absent (n ⫽ 92)

Mild (n ⫽ 44)

Severe (n ⫽ 30)

P

Absent breathing movements Absent body movements Abnormal amniotic fluid volume Nonreactive nonstress test Absent fetal tone

62 (67) 20 (13) 65 (70) 51 (55) 6 (7)

25 (57) 7 (16) 32 (73) 22 (50) 3 (7)

20 (67) 4 (21) 20 (67) 20 (67) 1 (3)

.46 .51 .85 .36 .79

Data are given as n (%). * According to Manning et al10 and subsequent modifications.11

found abnormal scores of BPP or its components associated with higher rates of clinical infectious outcome or laboratory evidence of AF infection.1–5 Those studies postulated that changes in fetal behavior were elicited by infection-associated mediators released in the intrauterine environment (amniotic cavity and placental circulation). Our study is based on the biologically plausible assumptions that the levels of such mediators would correlate with the severity of acute intrauterine inflammation. 13 Because it is unproven whether changes in BPP are secondary to the release of infectionrelated mediators, and because fetal behavioral changes might indicate intrauterine phenomena other than infection, alternative explanations should be sought. Three mediators have been hypothesized to influence changes in BPP—prostaglandin production, release of cytokines, and hypoxemia. Prostaglandins produced by the choriodecidua in response to bacteria might affect fetal movements, particularly breathing.14 Because prostaglandins are released early in preterm labor, a worsening BPP score in the context of PROM might signal impending labor rather than intrauterine infection.15 The published series did not control for presence of labor, so its effect cannot be assessed adequately. Cytokines, such as interleukin-1 and tumor necrosis factor, are released by residing macrophages in the presence of infection, have multiple biologic effects on the central nervous system and cardiovascular system, and potentially can affect fetal behavior.16,17 However,

documentation of an association between cytokines and BPP is lacking. Hypoxemia and acidosis are known causes of the loss of biophysical components.18 Because a significant association19 and lack of a significant association1,6 have both been reported between neonatal infection and cord pH, the discrepant conclusions of the published studies on BPP in PROM might indicate differences in rates of acidemic neonates. A study of 89 women with PROM in which BPP variables were assessed within 1 hour of amniocentesis and fetal blood sampling for microbiologic studies found that neither fetal activity nor AF volume predicted intrauterine infection.20 Umbilical venous blood gases were not different between infected and noninfected fetuses and were within the normal range, so the authors postulated that the BPP variables might be more affected by placental perfusion and fetal oxygenation than infection. That hypothesis would also reconcile the seemingly discrepant conclusions of studies using Doppler velocimetry in preterm PROM, which found that Doppler velocimetry indices of the umbilical artery were significantly different in women with PROM and inflamed placentas21 but not in those with fetal or intraamniotic infection22 compared with those with no evidence of infection. Noninvasive detection of intrauterine infection is desirable, but the optimal indicator of intrauterine infection remains elusive. Therefore, it is likely that ultrasonography will continue to be used to detect fetal

Table 5. Relationship Between Abnormal Biophysical Profile Components and Histopathologic Evidence of Acute Inflammation in Fetal Tissues Acute umbilical and/or chorionic inflammation

Abnormal biophysical profile parameter*

Absent (n ⫽ 71)

Mild (n ⫽ 46)

Severe (n ⫽ 49)

P

Absent breathing movements Absent body movements Abnormal amniotic fluid volume Nonreactive nonstress test Absent fetal tone

44 (62) 14 (20) 46 (65) 36 (51) 5 (7)

28 (61) 10 (22) 34 (74) 26 (56) 4 (9)

35 (71) 7 (14) 37 (75) 31 (63) 1 (2)

.47 .62 .37 .39 .35

Data are given as n (%). * According to Manning et al10 and subsequent modifications.11

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Table 6. Diagnostic Indices of the Biophysical Profile Components in Predicting Maternal or Fetal Severe Acute Inflammation Diagnostic index and biophysical profile score components* Sensitivity Amniotic fluid volume Breathing movements Body movements Nonstress test Fetal tone Specificity Amniotic fluid volume Breathing movements Body movements Nonstress test Fetal tone

Maternal SAI

Fetal SAI

P

67% (20/30) 67% (20/30) 13% (4/30) 67% (20/30) 3% (1/30)

76% (37/49) 71% (35/49) 14% (7/49) 63% (31/49) 2% (1/49)

.55 .85 .99 .95 .99

29% (39/136) 36% (49/136) 80% (109/136) 47% (64/136) 93% (127/136)

32% (37/117) 39% (45/117) 80% (93/117) 47% (55/117) 92% (108/117)

.71 .79 .99 .99 .93

SAI ⫽ severe acute inflammation. * Cutoffs chosen according to the score of Manning et al10 and subsequent modifications.11

infection. Because no single BPP parameter correlated with severity of intra-uterine infection, even the most sensitive individual BPP component, eg, nonstress test, would miss at least one third of cases of intrauterine infection (false negative), whereas even the most specific BPP component, ie, absent fetal tone, would result in a false-positive rate of at least 8%, with consequent unnecessary delivery of uninfected neonates at low gestational ages who would be exposed to complications and sequelae of preterm birth. Further prospective studies are needed to establish whether the trade-off between false-positive and false-negative results, which is implicit in treatment protocols of PROM based uniquely on ultrasonographic assessment of BPP,23 is clinically sound.

References 1. Vintzileos AM, Campbell WA, Nochimson DJ, Connolly ME, Fuenfer MM, Hoehn GJ. The fetal biophysical profile in patients with premature rupture of the membranes: An early predictor of infection. Am J Obstet Gynecol 1985;152:510 – 6. 2. Goldstein I, Romero R, Merrill S, Wan M, O’Connor TZ, Mazor M, et al. Fetal body and breathing movements as predictors of intraamniotic infection in preterm premature rupture of membranes. Am J Obstet Gynecol 1988;159:363– 8. 3. Roberts AB, Goldstein I, Romero R, Hobbins JC. Comparison of total fetal activity measurement with the biophysical profile in predicting intra-amniotic infection in preterm premature rupture of membranes. Ultrasound Obstet Gynecol 1991;1:36 – 40. 4. Roussis P, Rosemond RL, Glass C, Boehm FH. Preterm premature rupture of membranes: Detection of infection. Am J Obstet Gynecol 1991;165:1099 –104. 5. Romero R, Athayde N, Maymon E, Pacora P, Bahado-Singh R. Premature rupture of the membranes. In: Reece EA, Hobbins JC, eds. Medicine of the fetus and mother. Philadelphia: LippincottRaven, 1999:1581– 625.

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6. Vintzileos AM, Campbell WA, Nochimson DJ, Weinbaum PJ, Mirochnick MH, Escoto DT. Fetal biophysical profile versus amniocentesis in predicting infection in preterm premature rupture of the membranes. Obstet Gynecol 1986;68:488 –94. 7. Miller JM, Kho MS, Brown HL, Gabert HA. Clinical chorioamnionitis is not predicted by an ultrasonic biophysical profile in patients with premature rupture of membranes. Obstet Gynecol 1990;76:1051–3. 8. Gauthier DW, Meyer WJ, Bieniarz A. Biophysical profile as a predictor of amniotic fluid culture results. Obstet Gynecol 1992;80: 102–5. 9. Del Valle GO, Joffe GM, Izquierdo LA, Smith JF, Gilson GJ, Curet LB. The biophysical profile and the nonstress test: Poor predictors of chorioamnionitis and fetal infection in prolonged preterm premature rupture of membranes. Obstet Gynecol 1992;80:106 –10. 10. Manning FA, Baskett FA, Morrison I, Lange IR. Fetal biophysical profile scoring: A prospective study in 1184 high risk patients. Am J Obstet Gynecol 1981;140:289 –93. 11. Chamberlain PF, Manning FA, Morrison I, Harman CR, Lange IR. Ultrasound evaluation of amniotic fluid volume. Am J Obstet Gynecol 1984;150:245–9. 12. Salafia CM, Weigl C, Silberman L. The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies. Obstet Gynecol 1989;73:383–9. 13. Greig PC, Ernest JM, Teot L, Erikson M, Talley R. Amniotic fluid interleukin-6 levels correlate with histologic chorioamnionitis and amniotic fluid cultures in patients in premature labor with intact membranes. Am J Obstet Gynecol 1993;169:1035– 44. 14. Kitterman JA, Liggins GC, Fewell JE, Tooley WH. Inhibition of breathing movements in fetal sheep by prostaglandins. J Appl Physiol 1983;54:687–91. 15. Thompson PJ, Greenough A, Nicolaides KH. Fetal breathing movements and prostaglandin levels in pregnancies complicated by premature rupture of the membranes. J Perinat Med 1992;20: 209 –13. 16. Dinarello CA. Interleukin 1. In: Thomson AW, ed. The cytokine handbook. 2nd ed. London: Academic Press, 1994:31–56. 17. Tracey KJ. Tumor necrosis factor-alpha. In: Thomson AW, ed. The cytokine handbook. 2nd ed. London: Academic Press, 1994:289 – 304. 18. Vintzileos AM, Campbell WA, Nochimson DJ, Weinbaum PJ. The

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19.

20.

21.

22.

23.

use and misuse of the fetal biophysical profile. Am J Obstet Gynecol 1987;156:527–33. Vintzileos AM, Petrikovsky BM, Campbell WA, Rodis JF, Pinette MG, Egan JFX. Cord blood gases and abnormal fetal biophysical assessment in preterm premature rupture of the membranes. Am J Perinatol 1991;8:155– 60. Carroll SG, Papaioannou S, Nicolaides KH. Assessment of fetal activity and amniotic fluid volume in the prediction of intrauterine infection in preterm amniorrhexis. Am J Obstet Gynecol 1995;172: 1427–35. Yu¨cel N, Yu¨cel O, Yeleker H. The relationship between umbilical artery Doppler findings, fetal biophysical score and placental inflammation in cases of premature rupture of membranes. Acta Obstet Gynecol Scand 1997;76:532–5. Carroll SG, Papaioannou S, Nicolaides KH. Doppler studies of the placental and fetal circulation in pregnancies with preterm amniorrhexis. Ultrasound Obstet Gynecol 1995;5:184 – 8. Vintzileos AM. Antepartum surveillance in preterm rupture of membranes. J Perinat Med 1996;24:319 –26.

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Address reprint requests to:

Alessandro Ghidini, MD Georgetown University Medical Center Department of Obstetrics and Gynecology 3800 Reservoir Road, NW - 3PHC Washington, DC 20007 E-mail: [email protected]

Received December 9, 1999. Received in revised form March 2, 2000. Accepted March 30, 2000.

Copyright © 2000 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.

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