Hum. Reprod. Advance Access published online on November 22, 2007
Human Reproduction, doi:10.1093/humrep/dem375
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Different changes in resistance index between uterine artery and uterine radial artery during early pregnancy
1 Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Minamikogushi 1-1-1, Ube 755-8505, Japan 2 Department of Public Health, Yamagata University Graduate School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan
3 Correspondence address. Tel: +81-836-22-2286; Fax: +81-836-22-2287; E-mail: sugino{at}yamaguchi-u.ac.jp
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Abstract |
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BACKGROUND: Changes in blood flow impedance of the uterine artery (UA) and uterine radial artery (RA) which is in the lower-extremity of the UA were examined during early pregnancy.
METHODS: Blood flow impedance was assessed by transvaginal color-pulsed-Doppler-ultrasonography in 72 women from weeks 4–16 of pregnancy and expressed as a resistance index (RI).
RESULTS: RA-RI remained at the late-luteal phase level until the 5th week of pregnancy, decreased until the 7th week, and remained low until the 10th week. UA-RI remained at the late-luteal phase level until the 10th week, and then gradually decreased until the 16th week. In nine women with spontaneous abortion, five out of six women with impaired growth of the gestational sac showed high RA-RI at the 6th week of pregnancy, whereas all three women with loss of fetal heart beat at the 8th week showed normal changes in RA-RI.
CONCLUSIONS: Our results show different changes in blood flow impedance between the UA and RA during early pregnancy. A significant decrease of RA-RI after the 5th week may reflect vascular remodeling in the maternal–fetal interface at placentation, whereas a significant decrease of UA-RI after the 10th week may reflect changes of the whole uterine blood flow associated with uterine growth.
Key words: uterine blood flow/uterine artery/radial artery/early pregnancy/spontaneous abortion
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Introduction |
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Normal trophoblast invasion to the maternal decidua and decidual blood vessels is essential for successful placentation. In particular, dramatic changes in vascular structure occur in the maternal–fetal interface at placentation. Extravillous trophoblasts invade uterine spiral arteries, modifying their endothelial lining and media, and cause to a progressive dilatation of these vessels (Kam et al., 1999
). The vascular remodeling in the maternal–fetal interface may reduce local arterial resistance and thereby increase uteroplacental blood flow (Lin et al., 1995; Aardema et al., 2001; Prefumo et al., 2004a). Impairment of this process is associated with pregnancy complications including spontaneous abortion, intrauterine growth restriction and pre-eclampsia (Meegdes et al., 1988; Minguillon et al., 1989; Meekings et al., 1994; Vailhe et al., 1999; Aardema et al., 2001; Lisman et al., 2004; Prefumo et al., 2004a). In addition, increased uterine vascular resistance during the luteal phase decreases the pregnancy rate with in vitro fertilization and embryo transfer (IVF–ET) (Steer et al., 1992; Bassil et al., 1995). Uterine vascular relaxation and the increase in uterine blood flow in early pregnancy appear to be important determinants of pregnancy outcome.
Doppler ultrasound has been used for many years as a non-invasive technique to assess blood flow impedance. Although a number of studies have been reported regarding the change in uterine artery (UA) blood flow to assess uteroplacental circulation during early pregnancy, the findings given so far still seem to be controversial. Some study groups (Schulman et al., 1986; Thaler et al., 1990; Makikallio et al., 2004) reported no changes in UA blood flow until the 8–10th week of pregnancy and a rapid decrease thereafter. On the other hand, others reported a linear decrease in UA blood flow between gestational weeks 4 and 14 (Jurkovic et al., 1991; Jauniaux et al., 1992; Coppens et al., 1996; Valentin et al., 1996). Recently, much attention has been focused on the uterine radial artery (RA) that crosses the myometrium, which is the lower-extremity of UAs, because it is thought to better reflect the endometrial blood flow (Zaidi et al., 1995; Chien et al., 2002; Tamura et al., 2006). It is of interest to know whether blood flow impedance of RAs reflects vascular remodeling in the maternal–fetal interface at placentation, and whether abnormal blood flow patterns of RAs are associated with early pregnancy failure. However, the change in RA blood flow during early pregnancy is also controversial. Merce et al. (1996) reported that retrochorionic blood flow, which reflects RA blood flow, increased progressively between the 4th and 12th week of pregnancy. Makikallio et al. (2004) also reported that the pulsatility index of the RA decreased between the 5th and 10th week of pregnancy. On the other hand, Bernstein et al. (2002) reported that RA blood flow did not significantly change between the 4th and 12th week of pregnancy. Therefore, this study was undertaken to examine the change in blood flow impedance of the UA and the RA during early pregnancy.
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Materials and Methods |
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Patients
This study was reviewed and approved by the IRB of Yamaguchi University Graduate School of Medicine. From April 2004 to August 2006, a total of 106 women with a history of infertility, who were interested in becoming pregnant and had normal menstrual cycles, were recruited in this study. The mean age was 31.4 ± 5.4 years (mean ± SD), with a range of 23–42 years. They were non-smokers and free from major medical illness including hypertension. Women were excluded if they had myoma, adenomyosis, congenital uterine anomaly, ovarian tumor or used oestrogens, progesterone or androgens, or had chronic use of any medication, including non-steroidal anti-inflammatory agents or anticonvulsants. They received Doppler examinations during a natural menstrual cycle.
Out of 106 women, 63 women achieved a singleton pregnancy naturally (n = 33) or by the treatments [clomifene treatment cycle (n = 2), HMG–HCG treatment cycle (n = 14), IVF–ET treatment cycle (n = 14)], and nine women experienced a first-trimester spontaneous abortion. The mean interval between the first menstrual cycle studied and the last menstrual cycle followed by pregnancy was 6 months (2–18 months). The women with IVF–ET received ovarian stimulation followed by luteal support with HCG and progesterone. After pregnancy was confirmed, the women received longitudinal serial Doppler examinations weekly or every 2 weeks between the 4th and 10th week of pregnancy, and every 2–4 weeks between the 10th and 16th week of pregnancy. The day of ovulation, which was defined as the start of the 2nd week of pregnancy, was determined by ultrasonography, measurement of urinary LH or basal body temperature records.
Ultrasonography
Blood flow impedance of the UA and the uterine RA was evaluated with the use of a computerized vaginal ultrasonography with an integrated pulsed Doppler vaginal scanner [Aloka ProSound SSD-3500SV and Aloka UST-984-5 (5.0 MHz) vaginal transducer, Aloka Co. Ltd, Tokyo, Japan]. Uterine arteries were sampled lateral to the cervix near the internal os. Since RAs are in the lower extremity of UAs that cross the myometrium and are close to the endometrium, a mid-sagittal section of the uterus was obtained and RAs were identified in the middle of the myometrium. For pregnant women, trophoblastic tissue was detected in the gestational sac as a high echoic structure with abundant blood flow within the endometrial–myometrial interface. RA blood flow was detected within the myometrium close by trophoblastic tissue. The RA blood flow distribution pattern was determined by demonstrating pulsatile color signals in the myometrium as reported previously (Zaidi et al., 1995; Chien et al., 2002). After areas of maximum color intensity were selected, a Doppler range gate was applied and the pulsed Doppler function was activated to assess blood flow velocity. After confirming that waveforms were continuous, an average of 3–5 cardiac cycles was selected for calculation of the resistance index (RI): the difference between maximal systolic blood flow velocities and minimal diastolic flow velocities divided by the peak systolic flow velocities. RI was used to evaluate the pattern of blood flow impedance. The mean of bilateral UA-RI and the mean of the two points of RA-RI were used for statistical analyses. Measurements of RA-RI were performed until the 10th week of pregnancy. It is difficult to detect RA blood flow and to correctly measure RA-RI after the 10th week of pregnancy because of the technical problems since the distance between the sampling point and the vaginal transducer becomes longer as the uterus grows. Since the inter-observer coefficient of variation for Doppler flow measurements in the present study was <10%, which is consistent with the report by Ziegler et al. (1999), the Doppler flow measurements were judged to be reproducible.
Statistical analysis
The radial and UA-RI values were not distributed normally (Shapiro–Wilk test). Therefore, we used a non-parametric statistical analysis. The significance of differences in the mean values among more than two groups was estimated by the Kruskal–Wallis test followed by the Mann–Whitney U-test using the Bonferroni correction. A value of P < 0.05 was considered significant.
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Results |
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RA-RI values were significantly lower than UA-RI throughout the observational period (Fig. 1). In early pregnancy, RA-RI remained at the late luteal phase level until the 5th week of pregnancy, then significantly decreased until the 7th week, and remained low until the 10th week of pregnancy (Fig. 1). UA-RI remained at the late luteal phase level until the 10th week of pregnancy, and then significantly decreased until the 16th week of pregnancy (Fig. 1).
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The normal range of the RA-RI at the 5th and 6th week of pregnancy was defined as the range from the 10–90th percentiles of the normal pregnant women who achieved pregnancy naturally (Fig. 2, grey area). Figure 2 shows the changes in RA-RI between the 5th and 6th week of pregnancy in nine women with spontaneous abortion. Six women (cases a, b, c, d, e and g; Fig. 2) showed impaired growth of the gestational sac, and three women (cases f, h and i; Fig. 2) showed normal fetal growth and loss of fetal heart beat at the 8th week of pregnancy. Of the six women with impaired growth of the gestational sac, three showed abnormally high RA-RI at the 5th week of pregnancy (cases a, b and c; Fig. 2), and five of the six women showed high RA-RI at the 6th week of pregnancy (cases a, b, c, d and e; Fig. 2). These results suggest that high RA-RI has a role in failed pregnancies. On the other hand, all three women with loss of fetal heart beat at the 8th week of pregnancy (cases f, h and i; Fig. 2) showed normal changes in RA-RI between the 5th and 6th week of pregnancy. Two out of the nine women (cases c and g) did not show decreasing RI values between the 5th and 6th week of pregnancy, and they had impaired growth of the gestational sac (Fig. 2).
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Discussion |
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Our results show that the resistance to blood flow in the UA and RA each underwent different changes during early pregnancy. The significant decrease of RA-RI after the 5th week of pregnancy may reflect vascular remodeling in the maternal–fetal interface. This is because vascular remodeling by trophoblast invasion occurs at placentation, causing a reduction in local arterial resistance (Lin et al., 1995
; Aardema et al., 2001), although trophoblast invasion is limited to the endometrial part of spiral arteries at the early stage of pregnancy (Carter, 1997; Pijnenborg, 1998). It is also reported that the blood flow from the RA nearest to the placental site would be the indicator of the histological changes taking place in the implantation site (Merce et al., 1996). However, future studies are needed to determine the relationship between the Doppler RA resistance and histological features of vascular remodeling.
Our finding that the RA-RI decreased after the 5th week of pregnancy is consistent with previous reports that blood flow impedance of the RA decreased between the 4th and 12th week of pregnancy (Merce et al., 1996) and between the 5th and 10th week of pregnancy (Makikallio et al., 2004). However, our finding is not consistent with the report by Bernstein et al. (2002) that RA blood flow impedance did not significantly change between the 4th and 12th week of pregnancy. The differences among these reports including the present study may be due to the distinction between cross-sectional and longitudinal study designs.
Our finding of a significant decrease of UA-RI after the 10th week of pregnancy is consistent with previous reports of no changes in UA blood flow impedance until the 8–10th week of pregnancy and a rapid decrease thereafter (Schulman et al., 1986; Thaler et al., 1990; Makikallio et al., 2004). The decline of UA-RI may reflect the change of the whole uterine blood flow which is associated with uterine growth, because the major compartment of the uterus is the myometrium, and Doppler studies of UAs reflect the blood flow impedance of the myometrium rather than the local blood flow impedance of the endometrium (Ng et al., 2006).
The decreased RA-RI at the placental site whereas UA-RI remains constant may reflect the local development of the shunts at the placental site such as between spiral arteries and intervillous space, because a lower RI in the more distal part of the uteroplacental circulation indicates the development of such shunts (Makikallio et al., 2004). This suggests the possibility that the UA-RI was not affected because the change in RA-RI is a local event.
Early pregnancy loss is a common complication of pregnancy, but the mechanisms are poorly understood except when chromosomal abnormalities are involved (van Lijnschoten et al., 1994a,b; Genest et al., 1995; Jauniaux and Hustin, 1998; Roberts et al., 2000). Impairment of vascular remodeling in the maternal–fetal interface has been associated with pregnancy complications such as spontaneous abortion, intrauterine growth restriction and pre-eclampsia (Meegdes et al., 1988; Minguillon et al., 1989; Meekings et al., 1994; Vailhe et al., 1999; Aardema et al., 2001; Lisman et al., 2004; Prefumo et al., 2004a). Vascular remodeling and the following increase in uterine blood flow in early pregnancy appear to be important determinants of pregnancy outcome (Meekings et al., 1994; Aardema et al., 2001; Prefumo et al., 2004b). Doppler studies in the first trimester have failed to demonstrate abnormal blood flow indices in the uteroplacental circulation of pregnancies that subsequently ended in spontaneous abortion (Jauniaux et al., 2005). The present study showed cases of spontaneous abortion, with impaired growth of the gestational sac, whose RA-RIs remained high or failed to decrease normally between the 5th and 6th week of pregnancy. The high RA-RI between the 5th and 6th week of pregnancy may be a cause of spontaneous abortion and reflect impaired vascular remodeling caused by failure of normal trophoblastic invasion at placentation (Meegdes et al., 1988; Lisman et al., 2004; Jauniaux and Burton, 2005). Poor trophoblastic invasion and impaired modification of uterine spiral arteries have been associated with abnormally high UA Doppler resistance indices (Prefumo et al., 2004a). It is of interest to know when the high RA-RI started in these patients. Although the RA-RI may have been high from the preceding luteal phase, high RA-RI between the 5th and 6th week of pregnancy may be a useful marker of poor pregnancy outcome.
The present study showed that the changes in blood flow impedance during early pregnancy were different between UAs and uterine RAs. The significant decrease of RA-RI after the 5th week of pregnancy may reflect vascular remodeling in the maternal–fetal interface, although the trophoblast invasion is limited to the endometrial part of spiral arteries (Carter, 1997; Pijnenborg, 1998). On the other hand, the decrease of UA-RI after the 10th week of pregnancy may reflect the change in whole uterine blood flow. This study also reported cases of spontaneous abortion, with impaired growth of the gestational sac, whose RA-RIs remained high or failed to decrease normally between the 5th and 6th week of pregnancy. The altered change of RA-RI may give a new insight into understanding the early stages of the pathophysiology of spontaneous abortion, such as at the 5–6th week of pregnancy. However, further studies are needed with larger sample sizes.
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Funding |
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Scientific Research from the Ministry of Education, Science and Culture (Grants-in Aid 1779121, 18791158 and 19791153), Japan.
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Author Roles |
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Conception and design, acquisition of data, analysis of data and drafting the article—H.T.
Acquisition of data—I.M.
Acquisition of data—K.T.
Acquisition of data—R.M.
Acquisition of data—H.A.
Acquisition of data—T.T.
Acquisition of data—A.M.
Acquisition of data—Y.Y.
Statistical analysis—H.I.
Conception and design, interpretation of data, drafting the article and final approval—N.S.
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Submitted on April 23, 2007; resubmitted on October 9, 2007; accepted on October 23, 2007.
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