Objective
The objective of the study was to evaluate whether the time interval from corticosteroid administration to delivery is associated with variations in inflammatory/infectious markers in women with spontaneous preterm birth (SPTB).
Study Design
We conducted a secondary analysis of a prospectively collected cohort of women experiencing SPTB from 23 0/7 to 31 6/7 weeks. Patients were categorized by corticosteroid receipt and time interval until delivery. Prevalence of markers of inflammation and colonization/infection (cord blood interleukin [IL]-6 levels; Ureaplasma urealyticum [UU], Mycoplasma hominis [MH], and other anaerobic/aerobic cultures; histology of the placental disc, membranes and cord) were compared between groups using χ 2 and Mantel-Haenszel tests.
Results
Two hundred seventy-three patients had SPTB. Prevalence of elevated IL-6 ( P = .028) and positive UU/MH cultures ( P = .019) were highest in women not receiving corticosteroids and those delivering more than 7 days from receipt. The prevalence of both decreased in groups with delivery delayed at least 12 hours but increased as the interval lengthened to more than 48 hours. Overall positive placental cultures also nadired among those delivering at 12-24 hours after corticosteroids ( P = .049). As the interval increased, prevalence of acute inflammation at the rupture site increased ( P = .017). There were similar, but nonsignificant, increases in chorionic plate inflammation and funisitis.
Conclusion
The relationship between time interval from corticosteroids and evidence of inflammation in women experiencing SPTB is U shaped, suggesting earlier stages of inflammation in women with delayed delivery or transient decreases of inflammation in response to corticosteroids. This warrants further investigation to elucidate the natural history of SPTB and its modulation by corticosteroids.
Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality with an estimated incidence of 12% of births annually in the United States. Of these deliveries prior to 37 weeks’ gestation, spontaneous PTB (SPTB) accounts for the large majority (65-85%). It has been widely described in the literature that women with SPTB are significantly more likely to have signs of inflammation and even infection, including deciduitis, chorioamnionitis, villitis, and funisitis, than women with indicated preterm birth.
The mechanism of inflammation and infection in the pathogenesis of SPTB is not fully understood but involves a maternal immune response (possibly to bacterial invasion) stimulating the release of cytokines, prompting the production and release of prostaglandins and metalloproteinases, causing uterine contractions, rupture of membranes, and cervical collagen remodeling. Supporting these findings is the isolation of inflammatory markers such as tumor necrosis factor alpha, interleukin (IL)-1, IL-6, IL-8, and granulocyte colony-stimulating factor from serum, amniotic fluid, and cervicovaginal secretions.
Despite the increased knowledge regarding the pathogenesis of PTB, PTB still contributes to 75% of neonatal mortality and 50% of long-term childhood neurological impairment. The single most effective evidence-based intervention to decrease morbidity and mortality from PTB is the administration of antenatal corticosteroids for fetal maturity. In a 1994 consensus statement, the National Institutes of Health concluded that corticosteroid therapy decreases mortality, respiratory distress syndrome, and intraventricular hemorrhage in preterm infants. The described effects of corticosteroids were greatest 24 hours after administration; however, treatment of shorter duration was still suggested to be beneficial.
Although the intended role of corticosteroids for fetal maturation is clear, the effects of corticosteroids on inflammation associated with SPTB is less studied. Inflammation and infection (and their associated markers) are invariably associated with SPTB, but the impact of corticosteroids on these various markers of inflammation and infection, as well as the changes in inflammatory parameters with time from corticosteroid receipt, has not been described in the literature. Moreover, understanding the changes in these signs of inflammation and/or infection during corticosteroid therapy may help elucidate the natural history of SPTB or provide insight into methods to delay delivery. As such, our objective was to evaluate the association between the time interval from antenatal corticosteroid administration to delivery and variations in biochemical, microbiological, and clinical markers of inflammation and upper genital tract colonization/infection in women with SPTB.
Materials and Methods
In this study, we conducted a secondary analysis of a prospectively collected cohort of women experiencing preterm birth from 23 0/7 to 31 6/7 weeks’ gestation. Details of the study design and a variety of maternal and neonatal outcomes have previously been reported. In this original institutional review board–approved study conducted at the at the University of Alabama at Birmingham between December 1996 and June 2001 (grant HD33927), pregnancy history, maternal outcome, and neonatal outcome data were collected for maternal-infant dyads by trained research nurses.
In addition, a variety of markers of inflammation and infection were obtained. Umbilical cord blood IL-6 concentrations were measured according to a previously described protocol, with values greater than 34.5 pg/mL (95th percentile) deemed an elevation. Both umbilical cord and placental cultures for Mycoplasma hominis (MH), Ureaplasma urealyticum (UU), and other species of aerobes and anaerobes were performed as previously noted. Finally, placental evaluation was conducted by a single perinatal pathologist (O.M.F.-P.) according to a previously described histopathological protocol.
This institutional review board–approved secondary analysis was restricted to patients within the previously described cohort with SPTB, defined as delivery caused by the spontaneous onset of labor or preterm premature rupture of membranes (PPROM).
Patients with SPTB were categorized by corticosteroid receipt and, for those who received them, the time interval (in hours) from first dose of corticosteroids until delivery. Indications for delivery included labor, infection, placental abruption and bleeding, and fetal distress. The time intervals were divided as follows: patients delivering without corticosteroids, patients delivering less than 12 hours from first administered dose of corticosteroids, patients delivering between 12 and 24 hours of first dose, patients delivering between 24 and 48 hours, patients delivering between 48 and 168 hours, and patients delivering greater than 168 hours (7 days) from first administered dose of antenatal corticosteroids.
Markers of inflammation and upper genital tract colonization/infection were assessed at delivery including cord blood IL-6 levels; umbilical cord and placental cultures; and placental disc, membrane, and umbilical cord histology. For each indicator of inflammation, prevalence at different delivery time points was examined and compared using χ 2 and Mantel-Haenszel tests for trend.
Results
In the parent cohort, 457 women had a preterm birth, of which 293 patients had SPTB. A total of 273 of these 293 patients had complete information on corticosteroid administration and were included in this study. Fifty-two patients delivered rapidly or upon presentation and did not receive corticosteroids. Of the remaining 221 patients, 46 patients delivered within 12 hours of first antenatal corticosteroid dose, 9 between 12 and 24 hours of first dose, 28 between 24 and 48 hours, 90 between 48 and 168 hours, and 48 patients delivered greater than 168 hours (7 days) from first antenatal corticosteroid dose. Demographic characteristics and aspects of obstetric history are presented in Table 1 .
| Demographic | Patients (n = 273) a |
|---|---|
| Race | |
| Black | 161 (59) |
| White | 103 (38) |
| Hispanic/other | 9 (3) |
| Gestational age, wks | 28.0 ± 2.3 a |
| Married | 93 (34) |
| Education <12 y | 110 (40) |
| Male neonate | 147 (54) |
| Nulliparous | 139 (51) |
| Type of SPTB | |
| PPROM | 134 (49) |
| Spontaneous labor | 139 (51) |
a Represented as n (%), except gestational age represented as mean ± SD.
The relationship between the prevalence of each individual inflammatory/infectious marker and the time interval from first antenatal corticosteroid dose until delivery is summarized in Table 2 and represented graphically in Figures 1 and 2 . Multivariable adjustments are summarized in Table 3 . The prevalence of the elevated IL-6 concentrations was highest in women who did not receive corticosteroids (55.9%) and declined to a nadir of 5.9% in women delivering between 24 and 48 hours after their initial corticosteroid dose, after which the prevalence again increased to 48.5% in those delivered greater than 7 days from corticosteroid receipt ( P = .028).
| Variable | No CS | <12 | 12 to <24 | 24 to <48 | 48 to <168 | ≥168 | P value |
|---|---|---|---|---|---|---|---|
| n | 52 | 46 | 9 | 28 | 90 | 48 | |
| IL-6 | 55.9 | 37.5 | 40.0 | 5.9 | 42.0 | 48.5 | .028 |
| Cord UU/MH | 37.5 | 29.4 | 42.9 | 15.8 | 43.1 | 33.3 | .318 |
| UU/MH placenta | 43.8 | 42.2 | 33.3 | 29.6 | 62.5 | 58.7 | .014 |
| UU/MH either (cord or placenta) | 47.9 | 46.7 | 44.4 | 37.0 | 66.3 | 67.4 | .019 |
| Any positive placental culture | 68.8 | 71.1 | 33.3 | 66.7 | 80.7 | 76.1 | .049 |
| Acute inflammation at rupture site | 73.3 | 52.2 | 55.6 | 81.5 | 79.3 | 74.4 | .017 |
| Chorionic plate acute inflammation | 68.1 | 45.7 | 44.4 | 57.7 | 67.1 | 62.2 | .155 |
| Funisitis | 53.2 | 32.6 | 37.5 | 44.4 | 40.9 | 63.6 | .052 |
| Chronic inflammation of the membrane | 2.1 | 15.2 | 0.0 | 3.9 | 7.0 | 7.0 | .182 |
| Chronic inflammation of the decidua | 8.3 | 13.0 | 0.0 | 7.4 | 12.6 | 11.1 | .809 |
| Variable | <24 h a | 24 to <48 h a | >48 h a |
|---|---|---|---|
| IL-6 | 0.36 (0.12–1.08) | 0.04 (0.01–0.38) | 0.56 (0.25–1.28) |
| UU/MH placenta | 0.90 (0.39–2.11) | 0.47 (0.17–1.34) | 2.10 (1.03–4.26) |
| Acute inflammation at rupture site | 0.37 (0.15–0.91) | 1.48 (0.44–4.95) | 1.12 (0.49–2.53) |
| Chorionic plate acute inflammation | 0.39 (0.17–0.90) | 0.65 (0.24–1.78) | 0.88 (0.43–1.80) |
| Funisitis | 0.45 (0.20–1.05) | 0.70 (0.26–1.84) | 0.78 (0.39–1.55) |
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