Cytotrophoblastic invasion of the maternal spiral arteries and replacement of their the endothelium is central to the successful outcome of pregnancy, leading to the establishment of a low-resistance high-flow uteroplacental circulation. This process, known as physiologic transformation, begins as early as the 10th day after conception and continues throughout the pregnancy.1
The noninvasive assessment of uterine artery resistance by means of Doppler ultrasound has demonstrated that a high-resistance blood flow pattern is invariably present at the beginning of the pregnancy. As a result of the physiological transformation of the spiral arteries, a low-resistance pattern develops at varying gestational ages in different individual pregnancies. Previous research has demonstrated that the timing of trophoblastic invasion in the gestational interval between 19 and 26 weeks affects pregnancy outcome and birth weight of the child.2 However, increasing evidence suggests that the efficacy of the placentation process might be determined, at least in part, in the first trimester.3–7 The aim of this study was to investigate the relationship between the timing of disappearance of high-resistance uterine artery waveforms between the first and second trimester of pregnancy and birth weight.
MATERIALS AND METHODS
All pregnant women receiving antenatal care and delivered at our hospital between May 2002 and July 2003 were identified from our computerized clinical database. We included in our study all women with singleton pregnancies delivered at term who had uterine artery Doppler screening at both 11 to 14 weeks and 18 to 23 weeks of gestation. During the study period, first-trimester uterine Doppler assessment was performed in the setting of a clinical trial, whereas second-trimester uterine Doppler assessment was routinely available to all nulliparous women and to all parous women with risk factors for preeclampsia (previous pregnancy with preeclampsia or fetal growth restriction, concurrent maternal medical conditions, first pregnancy with new partner). Gestational age was calculated from the last menstrual period and confirmed by first-trimester ultrasound. The parity, smoking status, and ethnic group of the mother were recorded. Exclusion criteria were fetal chromosomal or structural abnormalities, concurrent maternal disease (eg, chronic hypertension, renal disease), and gestational diabetes. We identified pregnancies not complicated by preeclampsia and pregnancies in which severe preeclampsia developed. Preeclampsia was defined as a blood pressure more than 140/90 mm Hg and proteinuria of 300 mg or greater in 24 hours, or 2 readings of at least 1+ on dipstick analysis of midstream or catheter urine specimens if no 24-hour urine collection was available. Preeclampsia was defined as severe when delivery before 37 weeks of gestation was necessary for maternal or fetal indications. All pregnancy outcomes were obtained from the delivery suite database. The study was approved by the local institutional review board.
During ultrasound examination at 11–14 weeks, a midsagittal section of the uterus was obtained, and the cervical canal was identified. The probe was then moved laterally until the paracervical vascular plexus was observed. Color Doppler was turned on, and the uterine artery was identified as it turned cranially to make its ascent to the uterine body. Measurements were taken at this point, before the uterine artery branched into the arcuate arteries.8 During ultrasound examination at 18–23 weeks, the right and left uterine arteries were identified at the apparent crossover with the external iliac artery by the use of color Doppler. In all cases, when 3 similar consecutive waveforms were obtained, the presence or absence of a protodiastolic notch9 was recorded, and the total number of notches on both sides was calculated. All scans were conducted by attending physicians or registered sonographers using different models of ultrasound equipment (ATL, Bothell, WA; General Electric, Waukesha, WI; and Aloka, Tokyo, Japan).
The pregnancies were classified into 3 groups depending on the pattern of resistance to blood flow in the uterine arteries. Bilateral notching absent both at 11–14 and 18–23 weeks (group 1); bilateral notching present at 11–14 weeks but absent at 18–23 weeks (group 2); bilateral notching present at both the 11–14 weeks and 18–23 weeks scans (group 3).
Small for gestational age (SGA) was defined as a birth weight lower than the 10th customized percentile.10 Customized birth weight percentiles were calculated by using a freely downloadable software (Gardosi J, Francis A. Software program for the calculation of customized birth weight percentiles, 2000. Available at: http://www.gestation.net/gest/). For intergroup comparisons, one-way analysis of variance, the Tukey multiple comparison test, the χ2 test, and Fisher exact test were used as appropriate. Hierarchical multiple regression analysis was performed to investigate the relationship between the group of blood flow resistance, confounding variables, and birth weight. The first block of independent variables entered into the model included maternal age, maternal ethnicity (Caucasian/non-Caucasian), smoking status (smoker/nonsmoker), weight, height, gestational age at delivery, and fetal sex (male/female). The second block of variables added to the previous model included the uterine artery blood flow group, which were coded as dummy variables (group 2, group 3). All calculations were performed with the SPSS (SPSS Inc, Chicago, IL) and Prism (GraphPad Software Inc, San Diego, CA) software packages.
A total of 662 pregnancies not complicated by preeclampsia and satisfying the entry criteria were identified. Of these, 411 showed absent uterine artery notches or a unilateral notch at the 11–14–week scan (group 1). All these cases maintained a low-resistance uterine blood flow pattern at the second-trimester scan. Of the 251 pregnancies with bilateral notches at the 11–14–week scan, 222 subsequently displayed a low-resistance blood flow at 18–23 weeks (group 2), whereas only 29 maintained bilateral notches (group 3; Figure 1). The demographic and clinical characteristics of the 3 groups are shown in Table 1. The mean birth weight was 3,452 g (95% confidence interval [CI] 3,405, 3,498 g) in group 1, 3,310 g (95% CI 3,246, 3,373 g) in group 2, and 3,224 g (95% CI 3,076, 3,373 g) in group 3. The birth weight was significantly higher in group 1 than in groups 2 and 3 (Table 2 and Figure 2).
To discriminate the effect of uterine resistance from that of other confounding variables, a hierarchical multiple regression model was used. After adjusting for the other independent variables, the pattern of uterine resistance remained associated with birth weight (Table 3).
Table 4 shows the prevalence of SGA fetuses in each of the 3 study groups. SGA fetuses were twice as common in groups 2 and 3 compared with group 1 (P < .001).
During the study period, severe preeclampsia was observed in 6 cases. Of these, the pattern of uterine artery flow was classified in group 1 in 3 cases, group 2 in 1 case, and group 3 in 2 cases. The distribution among the 3 groups was not significantly different from that in pregnancies not complicated by preeclampsia.
The results of this study suggest that, in term pregnancies not complicated by preeclampsia, the timing of disappearance of high-resistance uterine artery waveforms between the first and second trimester is significantly correlated with the infant's weight at birth. The presence of a low-resistance uterine circulation at 11–14 weeks of gestation is associated with higher birth weights, whereas the presence of bilateral uterine artery notches at 18–23 weeks, suggesting a poorer trophoblastic invasion of the maternal spiral arteries, is associated with lower birth weights.
Interestingly, those pregnancies in which the switch from a high- to a low-resistance notching pattern occurred between the first- and the second-trimester (group 2), appear to have pregnancy outcomes that approximate to that of the higher resistance group, at least in terms of birth weight. In fact, the mean birth weight was significantly higher in group 1 than in groups 2 and 3, but no significant difference could be detected between the latter two. This finding remained unchanged even after correcting for other known determinants of birth weight, such as smoking status, gestational age at delivery, fetal sex, maternal height and weight, ethnic origin, and parity. The prevalence of SGA newborns in groups 2 and 3 was again very similar (about 14%) and almost double of that in group 1 (approximately 7%). Therefore, the presence of a low-resistance uterine artery flow pattern at the 11–14–week scan predicted a reduction in the risk of SGA, with an odds ratio of 0.42 (95% CI 0.25, 0.71). For this comparison, customized birth weight percentiles were used for the definition of SGA, which take into account maternal, gestational, and fetal factors and are more predictive of neonatal outcome than population-based standards.11
Doppler ultrasound investigation of the uterine arteries has been used for many years as a noninvasive technique to assess uterine vascular resistance and, indirectly, the progress of the physiological transformation of the decidual and myometrial vessels. Previous studies have shown an association between first-trimester uterine artery resistance and birth weight. Not only is a high-resistance pattern is associated with a higher incidence of intrauterine growth restriction,3–6 but even in normal pregnancies there is a correlation between uterine resistance indexes and weight at birth.12
However, the process of placentation is not an all-or-nothing phenomenon, and its temporal schedule may vary between different individuals and different pregnancies. Because most of the clinical interest has been concentrated on observations performed in the second trimester of pregnancy,13 the information available about the correlation between the timing of the variations in uterine artery flow and pregnancy outcomes is limited to late in the second trimester.2 The results of the present study suggest that, even in pregnancies that successfully present a low-resistance pattern of uterine resistance by the middle of the second trimester, the gestation at which this milestone is achieved has an effect on the final outcome of the pregnancy. Our data suggest that the earlier the reduction of resistance, the better the placentation process7,14,15 and the higher the birth weight.
There were no statistically significant differences between the group of late normalizers (group 2) and the cases where bilateral uterine notches were still present at 18–23 weeks (group 3). Even if a trend for a lower crude birth weight in group 3 were apparent (Table 2), detecting a difference in weight of 86 g at the 5% significance level with a power of 90% would require group 3 to include at least 200 subjects.16
Ideally, the timing of disappearance of high-resistance uterine artery waveforms between the first and second trimester should be assessed in regard to its association with preeclampsia,17 particularly the early-onset cases for which a stronger association with second-trimester uterine artery impedance has already been demonstrated.13 However only 6 cases of preeclampsia severe enough to need iatrogenic preterm delivery were observed during the study period and fulfilling the study entry criteria, which did not allow us to draw any conclusions on this subject.
The longitudinal variation in uterine artery blood flow pattern has a significant correlation with birth weight, likely reflecting the timing and degree of trophoblastic invasion of the maternal vessels. The potential clinical applications of this finding, with particular regard to the early identification of high-risk pregnancies, remain to be evaluated.
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