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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University of Berne-Inselspital, Bern, Switzerland;Department of Obstetrics and Gynecology, University of Insubria-Ospedale di Circolo, Varese, Italy; and Department of Obstetrics and Gynecology, University of Bari, Bari, Italy.
Address reprint requests to: Luigi Raio, MD, University of Berne-Inselspital, Department of Obstetrics and Gynecology, Schanzeneckstrasse 1, Bern, Switzerland; E-mail: luigi.raio @insel.ch.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Consecutive women admitted after 20 weeks’ gestation with the diagnosis of preeclampsia and whose fetus was normally grown (cases) were included in the study. Each case was matched to a healthy pregnant woman (controls) who had ultrasonography at the same gestational age (± 3 days). The sonographic cross-sectional areas of the umbilical cord and umbilical vessels were obtained in all patients and plotted on reference ranges. The umbilical artery resistance index was measured in all patients with preeclampsia.
RESULTS: Twenty-five preeclamptic women were enrolled. The proportion of cases with a lean (below the tenth centile) umbilical cord was higher in cases than in controls (12 of 25 versus 1 of 25, P < .001). The Wharton’s jelly area was lower in cases than in controls (median 105.8 mm2 [range 49.6–212.9 mm2] versus 138.7 mm2 [79.7–226.6 mm2], P = .024). The umbilical vein area was less in cases than in controls (median 29.2 mm2 [range 8.0–52.8 mm2] versus 37.4 mm2 [13.8–70.8 mm2], P = .032). The proportion of patients with a lean umbilical cord was higher among those with early-onset preeclampsia than in those with late-onset preeclampsia (12 of 19 versus 0 of 6, P = .014).
CONCLUSION: Early-onset preeclampsia frequently is associated with reduced Wharton’s jelly area and umbilical vein area compared with normal pregnancy. Sonographic umbilical cord morphometry might have clinical value for prompt identification of women at risk for preeclampsia.
Several studies have shown that umbilical cord morphology is influenced by several fetal and maternal conditions occurring during gestation ( Raio L, Ghezzi F, Di Naro E, Franchi M, Brühwiler H, Dürig P, et al. Sonographic measurements of the umbilical cord vessels areas in normal and small for date fetuses [abstract 59]. Am J Obstet Gynecol 2001;184:S27).1–4 Weissman and Jakobi3 reported an association between a sonographically large umbilical cord in the second trimester and gestational diabetes. Our group found that a sonographically lean umbilical cord in the second half of gestation was associated with a higher incidence of small for gestational age infants and fetal distress at the time of delivery.1,2 A histomorphometric study found that umbilical cords of growth-retarded fetuses had substantially different macroscopic and microscopic structures than umbilical cords of normally grown fetuses.4 Moreover, a morphometrically abnormal umbilical cord, easily detectable with a target sonographic examination, seems to be an earlier sign of fetal growth disturbance than fetal biometric measurements or umbilical artery Doppler flow parameters ( Raio et al. Am J Obstet Gynecol 2001;184:S27).1,4
Biochemical studies showed that the umbilical cord extracellular matrix was altered in women with pre-eclampsia.5,6 Bankowski et al5 and Pawlicka et al6 found that the Wharton’s jelly of preeclamptic women is characterized by a significant increase in sulfated glycosaminoglycans and type III collagen and a reduction of hyaluronic acid. The purpose of this study was to investigate whether the alterations in structural umbilical cord components observed after delivery in preeclamptic women have a sonographic counterpart during gestation. Although reference ranges for the umbilical cord cross-sectional area have been reported,7 we chose to generate new reference intervals for the umbilical cord cross-sectional area as a function of gestational age using a more appropriate statistical method.
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MATERIALS AND METHODS |
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After the nomogram was generated, a case-control study was designed to investigate the sonographic morphometric characteristics of women with and without preeclampsia. Consecutive pregnant women presenting between January 2000 and June 2001 with the diagnosis of preeclampsia at a gestational age greater than 20 weeks were considered eligible for the study. Inclusion criteria were singleton gestation, certain gestational age, absence of fetal congenital abnormalities, and presence of a three-vessel umbilical cord. Because a relationship has been observed between the presence of a lean umbilical cord and the delivery of a small for gestational age infant and oligohydramnios,1 women whose infant had a birth weight below the tenth centile for gestational age or oligohydramnios were excluded. Each case was matched to the next pregnant woman who had an ultrasound examination at the same gestational age (± 3 days), who had an uneventful pregnancy course until term gestation, and whose fetus was normally grown and healthy.
Preeclampsia was defined as systolic blood pressure over 140 mm Hg or diastolic blood pressure over 90 mm Hg and proteinuria of 0.3 g/L or more in a 24-hour urine collection period. Preeclampsia was considered severe when at least one of the following criteria was present: diastolic blood pressure of at least 110 mm Hg or a systolic blood pressure of at least 160 mm Hg on two occasions 2 hours apart, proteinuria of at least 5 grams in a 24-hour urine specimen, or oliguria of less than 500 mL in 24 hours.
All women were hospitalized at the time of diagnosis of preeclampsia and had a target sonographic evaluation to assess fetal well-being and umbilical cord morphometry. If a woman was scanned more than once during the hospitalization, only the measurements obtained at admission were considered. Each woman was included only once.
Gestational age was determined by reliable recollection of the last menstrual period and confirmed by an ultrasonographic examination within 14 weeks’ gestation. The measurements of the umbilical cord were obtained as previously described.8 Briefly, the sonographic cross-sectional areas of the umbilical cord, the umbilical arteries, and the umbilical vein were calculated at the maximal magnification. The ellipse function of the ultrasound machine was used in all cases, and the best-fitting ellipse was put over the umbilical cord and vessels. The surface cross-sectional area of Wharton’s jelly was computed by subtracting the total vessel area from the cross-sectional area of the umbilical cord. Intraobserver and interobserver variability were 4.3% and 5.1%, respectively.8 An umbilical cord was defined as lean if its cross-sectional area was below the tenth centile for gestational age. The umbilical artery resistance index was measured in all cases with preeclampsia.
All ultrasound examinations were performed with a Sequoia 512 machine (Acuson, Mountain View, CA) equipped with a 5-MHz transducer. Informed consent was obtained from all patients included in the study. The Human Research Review Committee approved this study.
Statistical analysis was performed using SPSS (SPSS Inc., Chicago, IL) and GraphPad Prism 3.00 for Windows, (GraphPad Software, San Diego, CA). The reference ranges for the umbilical cord area were constructed using the method described by Royston and Wright.9 Polynomial regression analysis was performed to identify the regression curves that best fit the mean and standard deviation (SD) of the umbilical cord area as a function of gestational age. Polynomial regression analysis was used for the SD of the umbilical cord area because the scaled absolute residuals appeared to show a trend with gestational age. The scaled absolute residuals were considered as the absolute value of the residual (difference between the measurements and the estimated curve for the mean) and multiplied by 1.25.
The standard deviation scores (z scores) were calculated using the formula (observed umbilical cord area measurement – mean umbilical cord area)/SD. To assess the model fit, the Gaussian distribution of the z scores was checked using the Kolmogorov-Smirnov test. Fifth and 95th, and tenth and 90th centiles for the umbilical cord area throughout gestation were obtained as previously described using the formulas mean ± 1.645 SD, and mean ± 1.28 SD, respectively.9 Student t test or Mann-Whitney U test were used to compare continuous variables, and proportions were analyzed with the Fisher exact test. Spearman rank correlation was used to investigate the relationship between the umbilical artery resistance index and the areas of the umbilical cord vessels. To allow comparisons among women enrolled at different gestational ages, the umbilical vein area:femur length ratio was calculated. We have chosen to use the femur length because its measurement is easily obtained, is highly reproducible, and takes into account not only the gestational age but also the size of the fetus. Statistical significance was set at P less than .05.
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RESULTS |
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The regression equation for the standard deviation (SD) according to gestational age (x) was
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The normal distribution of z scores was confirmed by the Kolmogorov-Smirnov test. Figure 1
shows the umbilical cord cross-sectional area observed measurements and the fitted fifth, tenth, 50th, 90th, and 95th centiles for gestational age.
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. No difference was found in the estimated fetal weight at the time of ultrasound between cases and controls. Similarly, at the time of ultrasound there were no significant differences between cases and controls in median (range) fetal biparietal diameter (80.6 mm [59.9–97.7 mm] versus 83.0 mm [56–99.1 mm]), abdominal circumference (240.6 mm [158.7–323.0 mm] versus 254.5 mm [170.1–331.6 mm]), and femur length (55.1 mm [38.5–69.5 mm] versus 57.0 mm [38.0–67.6 mm]). The birth weight of all fetuses whose mothers had preeclampsia was above the tenth centile for gestational age. Table 2 shows the umbilical cord sonographic morphometric characteristics of the study population. The proportion of cases with a lean umbilical cord was higher in cases than in controls (12 of 25 [48%] versus one of 25 [4%], odds ratio 20.3, confidence interval [CI] 2.35, 175.4; P < .001) (Figure 2). The proportion of fetuses with Wharton’s jelly area below the tenth centile for gestational age was lower among women with preeclampsia than among controls (ten of 25 [40%] versus one of 25 [4%], odds ratio 16.0, CI 1.85, 138.05; P = .004) (Figure 3). No difference was found in the proportion of fetuses with a lean umbilical cord between women with mild or moderate preeclampsia and those with severe preeclampsia (seven of 14 versus five of 11, respectively). On the contrary, the proportion of fetuses with a lean umbilical cord was significantly higher in cases with early-onset preeclampsia than in those with late-onset preeclampsia (12 of 19 [63.2%] versus zero of six, P = .014). Similarly, the proportion of fetuses with Wharton’s jelly area below the tenth centile for gestational age was higher in patients with early-onset preeclampsia than in those with late-onset preeclampsia (ten of 19 [63.2%] versus zero of six, odds ratio 14.3, P = .0508). Although the proportion of fetuses with a lean umbilical cord was significantly higher in women with early-onset preeclampsia than in controls (12 of 19 [63.2%] versus one of 25 [4%], odds ratio 42.8, CI 4.72, 389.1; P = .001), no difference was present in the percentage of fetuses with a lean umbilical cord between women with late-onset preeclampsia and controls (zero of six versus one of 25).
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DISCUSSION |
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The first finding of the present study is that morphometric alterations of the Wharton’s jelly are present in umbilical cords of fetuses whose mothers have early-onset preeclampsia. The most important aspect is that these changes are present in the absence of fetal growth disturbance and altered umbilical artery Doppler parameters. These results are supported by a recent study that reported a possible association between a reduced umbilical cord diameter in the first trimester and subsequent development of preeclampsia.10
The Wharton’s jelly is a metabolically active tissue involved in fluid exchange between the amniotic cavity and the umbilical vessels. The Wharton’s jelly is composed of an insoluble fibrillar network of different collagen types within which soluble open-coil polysaccharides are held. Of these, the most represented is hyaluronic acid, which can entrap large amounts of water. A smaller part of the Wharton’s jelly extracellular matrix is formed by sulfated glycosaminoglycans, which, in turn, are linked to proteins to form proteoglycans.10–13 Bankowski et al5 showed that preeclampsia is accompanied by a significant increase in the ratio of sulfated glycosaminoglycans to hyaluronic acid. Moreover, in vitro swelling of umbilical cord slices has been found to be influenced by the osmotically active polysaccharides that cause an expansion of the fibrillar network of the Wharton’s jelly. Adding hyaluronidase, an enzyme that digests hyaluronic acid, to the experimental system containing umbilical cord slices eliminated the approximately two-fold swelling observed for the untreated intact tissue in a phosphate-buffered saline solution.14 Cumulatively, these findings suggest that the Wharton’s jelly of preeclamptic women is characterized by reduced hydration. Therefore, it is reasonable to assume that a lean umbilical cord is the sonographic counterpart of these biochemical modifications.
The second observation of this study is that the umbilical vein size was smaller in preeclamptic women than in healthy pregnant women. Umbilical vessel development has been shown to be regulated by different factors, such as the action of locally acting substances, the vessels’ blood flow, and blood pressure.15–17 Because human umbilical cord vessels are unique in lacking innervation, the action of vasoacting substances seems to be crucial in controlling the tone of the umbilical vessels. The triggering event leading to preeclampsia is reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of the spiral arterioles.15 Placental ischemia is thought to lead to abnormal endothelial function, which results in enhanced formation of vasoactive substances. Several studies have noted that in established preeclampsia, the production of vasoactive substances, such as nitric oxide and endothelin-1, is altered compared with normotensive pregnancies.16,17
Finally, the results of the present study agree with those of Di Naro et al,2 who reported significantly smaller Wharton’s jelly cross-sectional area and umbilical vein area in fetuses with a lean umbilical cord compared with fetuses with a normal umbilical cord. In addition, fetuses with a lean umbilical cord have been found to have reduced umbilical vein blood flow compared with those with a normally grown umbilical cord.2 These findings are in keeping with Langille18 who found that a decrease in flow leads to impaired umbilical vessel development.
A possible limitation of the present study could be the small number of patients considered. Further larger prospective studies are needed to confirm the results of the present study.
In conclusion, we found that a macroscopic difference, visible in utero by ultrasound, exists between umbilical cords of healthy women and those with early-onset preeclampsia. Further prospective studies should investigate whether the detection of a lean umbilical cord early in gestation in otherwise healthy women might identify those at increased risk of preeclampsia.
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Footnotes |
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Received December 6, 2001. Received in revised form February 19, 2002. Accepted March 21, 2002.
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REFERENCES |
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2. Di Naro E, Ghezzi F, Raio L, Franchi M, D’Addario V, Lanzillotti G, et al. Umbilical vein blood flow in fetuses with normal and lean umbilical cord. Ultrasound Obstet Gynecol 2001;17:224–8.[Medline]
3. Weissman A, Jakobi P. Sonographic measurements of the umbilical cord in pregnancies complicated by gestational diabetes. J Ultrasound Med 1997;16:691–4.[Abstract]
4. Bruch JF, Sibony O, Benali K, Challer C, Blot P, Nessmann C. Computerized microscope morphometry of umbilical vessels from pregnancies with intrauterine growth retardation and abnormal umbilical artery Doppler. Hum Pathol 1997;28:1139–45.[Medline]
5. Bankowski E, Sobolewski K, Romanowicz L, Chyczewski L, Jawosrski S. Collagen and glycosaminoglycans of Wharton’s jelly and their alterations in EPH-gestosis. Eur J Obstet Gynaecol Reprod Biol 1996;66:109–17.[Medline]
6. Pawlicka E, Bankowski E, Jaworski S. Elastin of the umbilical cord arteries and its alterations in EPH gestosis (pre-eclampsia). Biol Neonate 1999;75:91–6.[Medline]
7. Raio L, Ghezzi F, Di Naro E, Gomez R, Mueller MD, Maymon E, et al. Sonographic measurements of the umbilical cord and fetal anthropometric parameters. Eur J Obstet Gynaecol Reprod Biol 1999;83:131–5.[Medline]
8. Ghezzi F, Raio L, Di Naro E, Franchi M, Balestreri D, D’Addario V. Nomogram of Wharton’s jelly as depicted in the sonographic cross section of the umbilical cord. Ultrasound Obstet Gynecol 2001;18:121–5.[Medline]
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11. Vizza E, Correr S, Goranova V, Heyn R, Angelucci PA, Forleo R, et al. The collagen skeleton of the human umbilical cord at term. A scanning electron microscopy study after 2N-NaOH maceration. Reprod Fertil Dev 1996;8: 885–94.[Medline]
12. Klein J, Meyer FA. Tissue structure and macromolecular diffusion in umbilical cord. Immobilization of endogenous hyaluronic acid. Biochim Biophys Acta 1983;22:400–11.
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14. Meyer FA, Silberberg A. In vitro study of the influence of some factors important for any physicochemical characterization of loose connective tissue in the microcirculation. Microvasc Res 1974;8:263–73.[Medline]
15. Carbillon L, Uzan M, Uzan S. Pregnancy, vascular tone, and maternal hemodynamics: A crucial adaptation. Obstet Gynecol Surv 2000;55:574–81.[Medline]
16. Norris LA, Higgins JR, Darling MR, Walshe JJ, Bonnar J. Nitric oxide in the uteroplacental, fetoplacental, and peripheral circulations in preeclampsia. Obstet Gynecol 1999;93:958–63.
17. Nishikawa S, Miyamoto A, Yamamoto H, Ohshika H, Kudo R. The relationship between serum nitrate and endothelin-1 concentrations in preeclampsia. Life Sci 2000; 67:1447–54.[Medline]
18. Langille BL. Remodeling of developing and mature arteries: Endothelium, smooth muscle and matrix. J Cardiovasc Pharmacol 1993;21(Suppl 1):S11–S17.
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