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Letters to the Editor |
Departments of1
Obstetrics and Gynecology and2
Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
3 Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan
aAddress correspondence to this author at: Department of Obstetrics and Gynecology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Fax 81-95-849-7365; e-mail kiyonori{at}nagasaki-u.ac.jp.
To the Editor:
Twin-twin transfusion syndrome (TTTS), which is a serious complication in monochorionic diamniotic twins (MCDA-T), involves unequal blood flow via the placental vascular anastomoses from the donor to the recipient twin. Although the placental anastomoses are present in all MCDA-T and both fetuses are genetically identical, TTTS occurs in only 15% of MCDA-T, and much of the pathophysiological basis of TTTS remains poorly understood. Clinically, a staging system based on the ultrasound features of TTTS is widely used for the management (1) but not for the prediction of TTTS. In addition, the known predictive findings observable by ultrasonographic examination are detectable only in a small portion of TTTS cases (2). New predictive markers are therefore desirable for the early detection and prevention of TTTS. Recently, placental mRNAs, such as human placental lactogen (PL) and some other hormones were detected in maternal plasma, and concentrations of each marker were measured with quantitative real-time reverse transcription (RT)-PCR (3)(4). Thus, circulating cell-free mRNA (cf-mRNA) in maternal plasma has become an attractive target for the noninvasive monitoring of pregnancy disorders (3)(5).
The purpose of the present study was to investigate the use of cf-mRNA concentration in maternal plasma as a predictive marker of later TTTS. The study participants included 17 pregnant women who visited the Obstetrics Clinic of Nagasaki University Hospital at 12–21 weeks of gestation for management of their pregnancy with MCDA-T. Included as a control group were 135 singleton pregnant women without medical complications at similar gestational age. All of the participants gave written informed consent, and the study was approved by the Research Ethics Committee of Nagasaki University. Although none of the 17 cases of MCDA-T were complicated by TTTS at the time of blood sampling, TTTS subsequently developed in 5 cases (TTTS group), but not in the remaining 12 cases (no-TTTS group). Gestational ages at diagnosis of TTTS were 15–25 weeks. The 3 groups had no significant differences in population characteristics, including the maternal age, the number of nulliparous women, and the gestational age at the time of sampling (data not shown).
The blood samples (8 mL) from each woman were collected into an EDTA tube, and the plasma sample was stored at –20 °C until use. After cf-mRNA was extracted from maternal plasma, a quantitative 1-step real-time RT-PCR assay was performed using an ABI 7900T Sequence Detector (Perkin-Elmer) as described previously (4). Primer sets and TaqMan probes for each gene and single-strand, and synthetic DNA oligonucleotides from each amplicon used for a calibration curve were prepared as described previously (4). Then, plasma concentrations of cf-mRNA for human PL and for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were measured and converted into multiples of the median (MoM) of the controls adjusted for gestational age, as described previously (5). The differences between the TTTS and the no-TTTS groups were evaluated with the Mann–Whitney U-test. Significant difference was defined as a P value <0.05.
The median (minimum–maximum) cf-PL mRNA MoM values were 1.80 (0.89–3.81) in the TTTS-group, 1.14 (0.77–1.35) in the no-TTTS group, and 1.00 (0.82–2.05) in the control group, respectively. At adjusted gestational age the cf-PL mRNA concentration was significantly higher in the TTTS group than in the no-TTTS group (Mann–Whitney U-test, P = 0.035), whereas there was no significant difference of cf-PL mRNA concentration between the no-TTTS group and the control group (P = 0.41; Fig. 1
). In addition, the median cf-GAPDH mRNA MoM value in the maternal plasma was significantly higher in the TTTS group (2.20; range 1.30–2.68) than in the no-TTTS group (1.09; range 0.68–3.25; P = 0.045). Our results suggested the possibility that unapparent pathophysiological changes had already occurred in the women who subsequently developed TTTS, although which specific conditions led to the increased mRNA in the maternal plasma in the TTTS group remain unknown.
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In conclusion, a quantitative aberration of both the cf-PL and cf-GAPDH mRNA in maternal circulation may be a novel predictive marker for TTTS, although both statistical differences were small and the sample size was too small to give sufficient strength to the analysis. Therefore, a combination of several cell-free placental mRNA markers could be effective for the prediction of TTTS, similar to the situation for tumor markers. Further study to identify gene transcripts that are expressed only in the placenta and not in blood cells may help to both predict and prevent TTTS and also may further elucidate the pathophysiology of this serious complication.
Acknowledgments
Grant/funding support: K.M. and N.N. were supported in part by Grants-in-Aid for Scientific Research (Nos. 19791155 and 17019055, respectively) from the Ministry of Education, Sports, Culture, Science and Technology of Japan, and N.N. was supported by Solution Oriented Research for Science and Technology from the Japan Science and Technology Agency.
Financial disclosures: None declared.
Acknowledgements: We thank Drs. Tadayuki Ishimaru, Joseph Wagstaff, Yoshisada Shibata, Akira Fujishita, and Makoto Murakami for their help and valuable advice.
References
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