Preterm labor fulfills all the criteria for a great obstetrical syndrome. For example, a sonographically short cervical length in the mid-trimester of pregnancy or high concentrations of fetal fibronectin in vaginal/cervical fluid are risk factors for subsequent spontaneous preterm labor and preterm birth 1–6. These criteria can be assessed weeks before the clinical recognition of spontaneous preterm labor and are hence suggested as predictors of preterm labor during a ‘subclinical stage’ or a ‘preclinical stage’. During this stage, pregnant women have abnormalities that may not be detected by a standard clinical examination 7.
This applies to clinically silent intrauterine infection weeks before the onset of preterm parturition. These preclinical infections have been detected at the time of routine mid-trimester amniocentesis for genetic indications in 0.4% of women and become clinically evident weeks later as either premature rupture of membranes or preterm labor 8–10. Also, fetal bacteremia has been detected in 30% of women with premature rupture of membranes and a positive amniotic fluid culture for microorganisms 11.
In the context of ‘multiple etiologies’ of preterm labor, other mechanisms of disease in preterm labor (i.e. ischemia/hemostatic disorders) may also be a direct causative factor. Maternal vascular lesions could lead to preterm labor by causing uteroplacental ischemia. Several epidemiological evidences support this concept. Arias et al.12 reported an odds ratio (OR) of 3.8 of the development of preterm labor for placental vascular lesions in the decidual vessels of the placenta. Abruptio placentae was found to be more frequent in women who deliver preterm 12,13. Women presenting with abnormal uterine artery Doppler velocimetry are more likely to deliver preterm than those with normal Doppler velocimetry 14,15. However, the precise mechanisms responsible for the onset of preterm parturition in women with uteroplacental ischemia have not been determined.
The aim of the current study was to assess the usefulness of a second trimester three-dimensional (3D) ultrasound measurement of placental volume and uterine artery Doppler indices in the prediction of preterm labor.
Materials and methods
This study involved 150 women with a singleton pregnancy between 20 and 24 weeks’ gestation attending Kasr El-Aini hospital during the period from October 2008 to May 2010. They ranged in age between 20 and 35 years. Women with intrauterine fetal death, induced preterm labor, or a premature rupture of membranes were excluded. The study was approved by the Local Ethical Committee of the Obstetrics and Gynecology department and all women provided fully informed consent.
After a full clinical examination and routine investigations, a 2D ultrasonographic assessment of fetal biometry and anatomy was performed. All women were subjected to 3D Doppler transabdominal ultrasonography using the Virtual Organ Computer-aided AnaLysis (VOCAL) technique to calculate the placental volume. Doppler examination of the uterine artery was performed to measure the pulsatility index (PI).
For the calculation of placental volume, the sweep angle was set at 85° and the probe was placed perpendicular to the placental plate. The placenta was examined and the size of the volume box was adapted in such a way that the placenta fitted into it completely. The volume was then stored for later offline analysis. The VOCAL technique was then used to obtain a sequence of six sections of the placenta, each taken after a 30° rotation from the previous one. In each of the six planes, the contour of the placenta was drawn manually, taking care to exclude the uterine wall, which at this gestation is usually thickened under the placenta, either because of hypertrophy or contraction. Each volume was measured twice; the machine calculated a volume from the areas highlighted in each of the six planes and when the calculation was completed, the computed reconstruction of the organ was displayed together with the volume.
The uterine artery was examined using CW Doppler. The probe was directed into the parauterine area in the region of the lower uterine segment. First color Doppler imaging is used to identify the uterine arteries close to the apparent crossover point of the uterine and external iliac arteries. The Doppler gate is then placed over the entire diameter of the uterine artery. Doppler flow velocity waveforms are recorded in five subsequent cycles and tracing for the calculation of the PI, to estimate placental resistance, is performed manually. The Doppler waveform is judged subjectively by the operator to have a notch if an early diastolic incisure can be seen in all five cycles. This procedure was carried out on both left and right uterine arteries. The mean of the two PI values was calculated.
All women were followed up until delivery. Delivery before 37 weeks’ gestation was considered preterm according to the definition of the American College of Obstetrics and Gynecology 16. The primary outcome measure was the onset of labor before 37 weeks’ gestation.
Data were analyzed using SPSSwin statistical package version 15 (SPSS Inc., IBM, Chicago, Illinois, USA). Numerical data were expressed as mean±SD. Qualitative data were expressed as frequency and percentage. The χ2-test (or Fisher’s exact test) was used to examine the relation between qualitative variables. For quantitative data, comparison between two groups was performed using the Student Mann–Whitney test. OR with a 95% confidence interval (CI) were used for risk estimation. Pearson’s product–moment was used to estimate the correlation between numerical variables. The receiver operating characteristic curve was used for the prediction of cut-off values. A P value less than 0.05 was considered statistically significant.
The mean age of the studied group was 26.9±4.6 years. Thirty-four women were nulliparous (22.7%). The mean gestational age at examination was 21.7±0.95 weeks. The mean placental volume was 352.5±18.5 ml (range 265–367 ml). The mean PI of the two uterine arteries was 1.46±0.09 (range 1.35–1.92). There was a significant negative correlation between the placental volume and PI of the uterine artery (r=−0.807, P<0.001) (Fig. 1). A diastolic notch was observed in four cases.
Preterm delivery occurred in 13 women (8.7%). Table 1 shows a comparison between two groups of women according to the time of delivery. Uterine artery PI was significantly higher in the preterm group (P<0.001). Meanwhile, placental volume was significantly smaller in the preterm group compared with the term group (P<0.001). The diastolic notch was observed in four cases. All of these cases delivered preterm.
Using the receiver operating characteristic curve, we found that a PI more than or equal to 1.5 during the second trimester had a sensitivity of 86.4% and a specificity of 88.3% to predict preterm delivery. The OR of high PI was 7.2 (95% CI: 4.3–12.1). A placental volume of 350 ml or less predicts preterm delivery with a sensitivity of 89.8% and a specificity of 100%. The OR of small placental volume was 38.6 (95% CI: 12.3–121.2). The combination of the two markers increases the sensitivity and the negative predictive value to 100%. Table 2 shows the reliability indices of the two studied markers, uterine artery PI and placental volume, separately and combined, for the prediction of preterm delivery. Placental volume more than 350 ml combined with PI less than 1.5 are considered protective in the prediction of preterm labor with an OR of 0.15 (95% CI: 0.04–0.55).
This study shows a new noninvasive marker for the prediction of preterm labor as early as mid-pregnancy. Using 3D power Doppler during the second trimester, we can predict preterm delivery with a total accuracy of almost 99%. Placental volume less than 350 ml combined with PI more than or equal to 1.5 had a sensitivity of 100% for the prediction of preterm delivery. The absence of the two signs is an important sign with an OR of 0.15 (95% CI: 0.04–0.55).
Human parturition is suggested to involve anatomical, physiological, biochemical, endocrinological, immunological, and clinical events that occur in the mother and/or the fetus in both term and preterm labor. For spontaneous preterm labor, Romero et al.17 have classified patients into two groups: those with inflammatory lesions of the placenta and membranes and those without evidence of inflammation. In fact, the noninflammatory group represents a challenge in the identification of the mechanisms responsible for preterm parturition. In this group, the placenta usually shows vascular lesions indicating the failure of physiological transformation of the myometrial segment of the spiral arteries, atherosis, and thrombosis of the spiral arteries 17.
Normal placentation is a prerequisite of normal pregnancy. Abnormal placentation may cause either lower levels of O2, with resulting villous hypervascularization, as seen in pre-eclampsia, or higher than normal levels with abnormal branching and fetal growth restriction 18,19. In the current study, we tested the hypothesis that a low placental volume and a high PI of uterine arteries with the resultant uteroplacental ischemia may be a noninflammatory trigger for preterm labor.
Many studies have used low placental volume in the first trimester for the prediction of adverse pregnancy outcomes including a small-for-gestational-age fetus, pre-eclampsia, and pregnancy-induced hypertension; however, the results are controversial 20–24. Most studies suggest that a low birth weight is often preceded by a low placental volume in the second trimester 25–27. However, Hafner et al.28 showed that 3D ultrasound placental volume measurement in the second trimester is not a satisfactory technique for predicting small for gestational age infants.
Many recent studies have used uterine artery Doppler ultrasonography for the prediction of an adverse pregnancy outcome. It had a high negative predictive value for the prediction of pre-eclampsia, placental abruption, and low birth weight 29.
Papageorghiou and Leslie 30 reviewed studies examining uterine artery Doppler findings in women with adverse pregnancy outcomes. Doppler at 23 weeks predicted almost two-thirds of early stillbirths. A systematic review that included 133 studies with a total of 41 431 patients found that uterine artery Doppler ultrasonography predicts pre-eclampsia, the maternal consequence of placental disease, more confidently than intrauterine growth restriction. Increased PI with notching in the second trimester best predicted overall pre-eclampsia in low-risk and high-risk patients 31.
We could not find articles discussing the use of placental volume for the prediction of preterm labor and delivery. The current study may be the first to suggest the combination of a uterine artery Doppler study with placental volume measurement for this purpose. Owing to the small sample size, this study may be considered a pilot study. Larger surveys are required for the confirmation of these findings and for more accurate estimation of cut-off values of the two markers.
Conflicts of interest
There are no conflicts of interest.
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