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Technical Briefs |
1 University Women’s Hospital/Department of Research, University of Basel, Basel, Switzerland
2 Department of Medical Genetics, Sun Yat-Sen University, Guangzhou, Peoples Republic of China
3 The Second People’s Hospital of Tibet, Lhasa, Tibet, Peoples Republic of China
4 Lhasa Maternal and Child Health Hospital Tibet, Lhasa, Tibet, Peoples Republic of China
5 Department of Gynaecology, Maternal and Children’s Hospital of Guangdong Province, Guangzhou, Peoples Republic of China
6 Department of Anatomy II, University Hospital, RWTH, Aachen, Germany
aaddress correspondence to this author at: Laboratory for Prenatal Medicine, University Women’s Hospital/Department of Research, Spitalstrasse 21, CH 4031 Basel, Switzerland; fax 41-61-325-9399, e-mail shahn{at}uhbs.ch
Pregnancy at high altitude (>2700 m) is characterized by the delivery of smaller than average babies (birth weight may decrease by as much as 100 g per 1000 m increase in altitude), as well as an increased incidence of intrauterine growth restriction and preeclampsia (1)(2)(3). The placenta also exhibits clear morphologic changes, which may represent a compensatory adaptation to facilitate adequate transfer of oxygen to the fetus, in that the terminal villi display increased vascularization and thinning of the syncytiotrophoblast layer (4)(5).
Previous studies have indicated that circulating fetal DNA concentrations in maternal plasma are increased in pregnancies affected by preeclampsia (6)(7), fetal growth restriction (8), or preterm labor (9); pregnancies with aneuploid fetuses (10)(11); and pregnancies affected by other pregnancy-related disorders involving an underlying placental pathology (12)(13). This has led to the suggestion that abnormalities in placentation may be associated with increased liberation of fetal DNA into the maternal circulation (14)(15).
For this reason we investigated whether circulating fetal DNA concentrations are affected in pregnancies at high altitude. Furthermore, because it has also been reported that ethnic groups that have adapted to living at high altitudes for centuries or millennia, e.g., native Tibetans, have better pregnancy outcomes than recent migrants, e.g., Han Chinese (16), we examined samples obtained from ethnic Tibetans and recent migrant Han Chinese residents in Lhasa (altitude, 3650 m) and compared them with samples from Han Chinese living at sea level.
Approval for this study was granted by the Chinese Governmental Authorities in Guangzhou, Guangdong Province, and Lhasa, Tibet. Written informed consent was obtained before donation of an 8-mL venous blood sample. All samples were obtained shortly before delivery and processed on site (Guangzhou and Lhasa); the plasma samples were stored frozen until use. Plasma samples from Lhasa were air-freighted frozen to Guangzhou for analysis. Previous studies have shown that the shipping of maternal plasma samples under conditions similar to those we used for this study does not lead to significant differences in circulating fetal DNA concentrations compared with samples processed locally (7)(10)(11). All plasma samples were analyzed under identical conditions in parallel at the Division of Medical Genetics, Sun-Yat University, Guangzhou, China, by real-time PCR as described previously (7). Strict anticontamination procedures were used throughout, and no false-positive results were recorded. The data acquired in Guangzhou were analyzed at the University of Basel (Basel, Switzerland) by use of SPSS® and Microsoft Excel® software packages. Significance for these nonparametric data were determined by the Mann–Whitney test.
We examined circulating fetal DNA concentrations in Han Chinese (n = 19) with noncomplicated pregnancies at sea level in comparison with recently migrant Han Chinese (n = 21) as well as ethnic Tibetans (n = 27) living in Lhasa (altitude = 3650 m; Table 1
). We also examined the possible influence of preeclampsia at high altitude on circulating fetal DNA concentrations in both Han Chinese (n = 11) and ethnic Tibetans (n = 15; Table 1
). Preeclampsia was determined by a blood pressure of 
140/90 mmHg in two determinations 4 h apart or by a diastolic blood pressure of 110 mmHg and an associated proteinuria of 300 mg/48 h after 20 weeks of gestation in previously normotensive women, as described previously (7).
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Our analysis indicated that concentrations of circulating fetal DNA were significantly increased by a factor of almost 4 in the high-altitude pregnancies compared with the control cohort at sea level (Table 1
and Fig. 1A
). For women with noncomplicated pregnancies, we observed no significant difference between ethnic Tibetans and migrant Han Chinese living in Lhasa with regard to circulating fetal DNA concentrations (Table 1
and Fig. 1A
) or fetal birth weight (Table 1
). In those pregnancies at high altitude that were affected by preeclampsia, we observed an additional significant increase in circulating fetal DNA in both population groups (Table 1
and Fig. 1B
). Again, we found no significant difference in fetal DNA concentrations between these two groups. What is clear, however, is that even under these conditions at high altitude, preeclampsia is associated with an increment in circulating fetal DNA concentrations, in a manner similar to what has been reported previously in studies conducted at lower altitudes (6)(7).
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Our findings are of interest because they indicate that the placental changes that occur at high altitude are mirrored in the release of cell-free DNA by these tissues, concurrent with the attempt to adapt to and overcome the lowered oxygen tension. Of further interest is that no significant difference in circulating fetal DNA concentrations was discernable between ethnic Tibetans and recent migrant Han Chinese. This finding is rather unexpected because previous studies have supported the hypothesis that ethnic populations, such as Tibetans who have lived for almost 5 millennia at high altitude, have adapted to low oxygen concentrations and consequently have better pregnancy outcomes than do newly arrived migrant populations (16). We did not observe any influence of ethnicity concerning the release of fetal DNA, which suggests that the underlying placental alterations are similar in both groups. What does seem likely, however, is that residents who have lived for extended periods at high altitudes have developed optimal strategies for adapting their placental tissues to the underlying deficiencies to ensure an optimal pregnancy outcome (16). This may be reflected in the increased occurrence of intrauterine growth restriction in Han Chinese at high altitude, in contrast to native Tibetans, a trend we also observed in our study. i.e., babies born to Han Chinese women living at high altitude were smaller than those born to Han Chinese women living at sea level. We also observed some evidence of a further reduction in fetal weight for babies born to Han Chinese women with preeclampsia at high altitude, whereas no such difference was apparent in comparable Tibetan study groups. These findings will, however, need to be confirmed in larger studies.
In summary, analysis of circulating fetal DNA may not only be useful for the noninvasive prenatal assessment of fetal genetic traits; in the future, it may also be a unique tool for the study of anomalous placentation. In this context it will be interesting to determine whether circulating fetal RNA concentrations behave in a similar manner in pregnancies at high altitude.
References
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