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Technical Briefs |
1 Laboratory for Prenatal Medicine, University Women’s Hospital, and Department of Research, University Hospital Basel, Basel, Switzerland;2 University Women’s Hospital, University Hospital Basel, Basel, Switzerland;
aaddress correspondence to this author at: Laboratory for Prenatal Medicine, University Women’s Hospital, University Hospital Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland; fax 41-61-265-9399, e-mail shahn{at}uhbs.ch
Several studies using quantitative real-time PCR to measure fetal DNA and mRNA in maternal plasma have suggested that their concentrations could indicate the presence of certain pregnancy-related disorders or predispositions to them (1). Significant increases in the median concentration of cell-free fetal DNA have been reported in pregnancies bearing aneuploid fetuses (2)(3), in those affected by or at risk for preeclampsia (4)(5)(6)(7)(8), or those with preterm labor (9). Fetally derived corticotropin-releasing hormone (CRH) mRNA is reportedly increased in pregnancies with manifest preeclampsia (10), and human chorionic gonadotropin ß-subunit mRNA has been reported to be increased in pregnancies with aneuploid fetuses (11).
In this study, we measured CRH mRNA by a real-time quantitative reverse transcription-PCR assay (10)(12) in women with preterm labor. Preterm delivery remains a leading cause of perinatal mortality, has an unchanged incidence of almost 7% over the past decade (13)(14), and has no known etiology. No test can identify those pregnant women with preterm contractions who will deliver prematurely and those who will respond to treatment (14).
We performed a retrospective analysis of circulatory CRH mRNA concentrations in samples we had collected for the assessment of fetal cell trafficking in pregnancies with preterm labor (15). The definition of preterm labor was made in accordance with those of the Canadian preterm labor investigations group (14). All samples were collected at a median of 26 weeks of pregnancy (range, 19–33 weeks). Tocolytic treatment was carried out with hexoprenalin, a ß-sympathomometic (15). In addition, all women with preterm contractions received an in utero glucocorticoid application at the time of blood sampling to assist with fetal lung maturation (15). Exclusion criteria included pregnancies with known fetal malformations and those women who had received previous glucocorticoid treatment (15). Of the original study cohort, three cases had premature rupture of membranes, six cases had vaginal bleeding, and four fetuses were intrauterine growth retarded (15). No invasive procedures were performed during the time of the study (15).
In our current analysis, of the 35 cases with preterm labor, 11 women delivered prematurely (median gestational age at delivery, 33 weeks), and 24 responded to tocolytic treatment and delivered at term (median gestational age at delivery, 38 weeks). Fifteen matched control cases who all delivered at term were included in our current analysis. mRNA was extracted from 800 µL of plasma stored frozen at –80 °C by use of TRIzol LS Reagent (Invitrogen) and commercial column technology (Qiagen). CRH mRNA concentrations were quantified by real-time reverse transcription-PCR as described previously; results are reported in copies per mL of maternal plasma (10)(12). The data were analyzed by use of SPSS for Windows, and the Mann–Whitney U-test was used to determine significance of differences between the study and control groups (9). The results are presented in Fig. 1
as box plots.
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Circulatory CRH mRNA was not significantly higher (P = 0.09) in the group with preterm contractions (n = 35; median, 81 copies/mL; range, 11–6285 copies/mL) than in the control cohort (n = 15; median, 38 copies/mL; range, 17–147 copies/mL). Circulatory CRH mRNA concentrations were, however, higher than in controls in the subgroup that delivered prematurely despite treatment (PTD group; n = 11; median, 100 copies/mL; range, 19–743 copies/mL; P = 0.003), but not in the treated group that delivered at term (TD group; n = 24; median, 66 copies/mL; range, 11–6285 copies/mL; P = 0.502; Fig. 1
). This effect was apparent, although four cases with very high circulatory CRH mRNA were noted in the TD group (range, 1392–6265 copies/mL). Despite this apparent anomaly concerning the TD group, our overall analysis nevertheless suggests that the analysis of circulatory CRH mRNA concentrations may assist in distinguishing between pregnancies with true preterm delivery and those that respond to tocolysis. It should be noted, however, that such an assessment will not be 100% specific.
In this regard, our data are in very close agreement with the previous report by Leung et al. (9), who reported increased median fetal DNA concentrations in eight pregnant women with preterm labor in whom tocolytic treatment was not effective when compared with six women who responded to tocolysis. The major differences between these two studies are that our study was based on a larger cohort and could be performed in a gender-independent manner, unlike the previous study, which was restricted to the analysis of male fetal DNA in the maternal blood (9).
In conclusion, the remarkably similar combined data from these two independent studies suggest that analysis of circulatory fetal nucleic acids may assist obstetricians in identifying pregnant women with an increased risk of preterm labor who do indeed deliver prematurely.
References
The following articles in journals at HighWire Press have cited this article:
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  X. Y. Zhong, S. Gebhardt, R. Hillermann, K. C. Tofa, W. Holzgreve, and S. Hahn Parallel Assessment of Circulatory Fetal DNA and Corticotropin-Releasing Hormone mRNA in Early- and Late-Onset Preeclampsia Clin. Chem., September 1, 2005; 51(9): 1730 - 1733. [Full Text] [PDF]
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