Reference values for umbilical cord diameters in placenta specimens

1 2 3 Reference values for umbilical cord diameters in placenta specimens H. Pinar 1, Murat Iyigün 2 4 5 6 7 8 9 10 Halit Pinar, MD Brown Medical School Women and Infants Hospital Division of Perinatal Pathology 101 Dudley Street Providence, Rhode Island 02905 11 12 13 14 15 Murat Iyigün, PhD University of Colorado Department of Economics Boulder, CO 16 17 18 Corresponding Author: Halit Pinar, MD 1

19 20 21 22 23 24 25 26 27 Division of Perinatal and Pediatric Pathology Brown Medical School-Women and Infants Hospital 101 Dudley Street Providence, RI, 02905 Phone: (401) 274-1122 1190 Fax: (401) 453-7681 hpinar@wihri.org Running Title: reference values for umbilical cord diameters in placenta specimens 2

28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Abstract Context To determine the normal values for umbilical cord diameters in placenta specimens. Methods We retrospectively collected values of umbilical cord diameters from 973 placenta specimens examined in the Division of Perinatal Pathology at Brown University. The specimens were examined using the same standard protocol during the calendar years 2005 t0 2007. Gestational ages of the newborns ranged from 20-41 weeks. Placentas originated from pregnancies associated with any condition known to cause fetal growth impairment were excluded. In addition, cases without complete clinical or pathological information and samples from multifetal gestation, or with developmental abnormalities such as umbilical cord masses were also excluded. The longest diameter of umbilical cords representative of the entire sample was measured and recorded. Since only cord segment(s) close to the placental insertion site were received in the laboratory, the measurements were obtained from these samples. No measurements were available from the remainder of the cords left with the newborns. To establish the 3

46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 link between umbilical cord diameters and gestational age, polynomial regression analysis was conducted. Results Measurements from 973 singleton placentas were used in the statistical estimates and distribution of normal values throughout gestation was calculated. The regression equation was y = - 11.9994 + 1.33966x -.018231x 2 where y denotes the umbilical cord diameter in millimeters and x is gestational age in weeks. A statistically significant non-linear relationship was found between umbilical cord diameters and gestational age. The direct measurements of umbilical cords during the pathological examination were smaller than the ultrasound measurements by 30-40% over the gestational age range of 20 to 41 weeks. Conclusions Reference values for umbilical cord diameters in placenta specimens were determined and their distribution according to gestational ages was calculated. Our nomograms are novel and derived from the pathological specimens rather than in vivo ultrasound examinations. Therefore, instead of published reference values of umbilical cord thickness in the pathology literature, which reflect in vivo 4

64 65 ultrasound measurements, we recommend that the values collected from placental specimens should be used. 5

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 Introduction Ultrasonographic evaluation of the fetus is very significant in the obstetrical management. In addition to fetal parameters it includes placental measures such as umbilical cord length, diameter, and degree coiling among others [1-8]. The values obtained in the ultrasonographic evaluation are compared with normal reference values allowing certain diagnoses. For example thin umbilical cords have been associated with fetal growth impairment. A study comparing growthrestricted fetuses with an appropriate for gestational age group has shown that the cross-sectional area of all components of the umbilical cord is reduced in the former [9-10]. In pregnancies complicated by early pre-eclampsia, the crosssectional areas of the Wharton jelly and umbilical vein were found to be reduced in comparison to normal pregnancies [11-13]. An increase in the umbilical cord diameter has been described in pregnancies complicated by gestational diabetes, various causes of macrosomia and aneuploidies [7, 14-15]. Evaluation of the umbilical cord is also an essential part of the pathological examination of the placenta. Proper macroscopic examination technique includes measurement of the length and diameter of the umbilical cord among other features [16-21]. Although most of the normal reference values for placental 6

84 85 86 87 88 89 90 91 92 93 parameters were derived from pathological samples, umbilical cord diameter was not [19-21]. They have been derived from various studies that used ultrasonography in ongoing pregnancies [18-21]. Umbilical cords in vivo are active vascular conduits connecting the placenta to the fetus and hemodynamically active. Measurements obtained in vivo reflect active blood flow in the umbilical vessels. Blood flow keeps the vessels patent and prevents them from collapse. After delivery, blood flow ceases and the vessels constrict and collapse. These changes affect the shape and dimensions of the umbilical cord. The purpose of this study was to define the reference values of umbilical cord diameters between 20 and 41 weeks gestational ages using placental samples. 94 95 96 97 98 99 100 101 Materials and method Population We retrospectively reviewed 5,499 placenta specimens that were examined during the years 2005-2006 using the same standard protocol by the Division of Perinatal Pathology at Brown University. Medical records were reviewed for demographic characteristics, maternal antepartum history and associated complications, birth data and neonatal findings. The pathology records of the placenta specimens were also examined and data extracted. 7

102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Inclusion and exclusion criteria The criteria for placental examination at Women and Infants Hospital include similar conditions to the College of American Pathologists (CAP) recommendations (Table 1) [17]. Since our objective was to collect a cohort as normal as possible, any sample from a mother with any condition that has been associated with fetal or placental growth impairment has been excluded from the study. In addition, cases without complete clinical or pathological information and samples from multifetal gestation, or with developmental abnormalities such as umbilical cord masses were also excluded. Since placentas from term and uncomplicated pregnancies routinely were not sent to the Laboratory to be examined, 503 term placentas were randomly chosen and records reviewed. 372 of these placentas were included in the study. Macroscopic examination of the placenta Placentas were examined fresh using a standard method. After inspection, the umbilical cords were trimmed leaving a stump at the insertion site measuring 0.5-1 cm. Next, the membranes were examined and trimmed. The trimmed placental disc was weighed after draining all the blood. The longest and shortest diameters of the placental disc were measured. After the placental disc was sliced into 1 cm thick slices, thickest and thinnest slices were measured. 8

121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 Measuring and sampling of the umbilical cords The length of all the received cord segments was measured. The umbilical cord segment closer to the insertion site to the placental disc was designated as the placental end (proximal end). The opposite segment towards the fetus was designated as the fetal end (distal end). Only the segments of the umbilical cords close to the placental insertion site (proximal) were available for examination. Irrespective of the shape of the cross section, the longest diameter representative of the entire umbilical cord sample was measured and recorded (Fig. 1). Data Analysis Data were collected into a central database and analyzed using Stata Version 9.2 (2006, StataCorp LP, College Station, TX). We derived our baseline estimates using a non-linear (polynomial) Ordinary Least Square regression (OLS). We included gestational age as the main explanatory variable (x) and umbilical cord diameter measures as the dependent variable (y). We allowed gestational age to enter the empirical specifications non-linearly (i.e., we included x 2 as a separate explanatory variable). This is done to capture a potentially non-linear relationship between gestational age and umbilical cord diameter, whereby the growth rate in the umbilical diameter can vary over gestational time. The distribution of the data by gestational age is summarized in Table 2. As shown, the average umbilical 9

140 141 cord diameters peak during the 37 th week and then drop somewhat in the remaining four weeks. 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 Results During the study period, a total of 5, 499 placenta specimens were examined between 20 and 41 weeks of gestation. 973 (17.7%) specimens met the inclusion criteria. Maternal ages ranged from 18-49 years, whereas the median parity was two, ranging from zero to five. In all the 973 cases included in the study, estimated date of confinement was determined based on an accurate last menstrual period and confirmed by a first- or second-trimester sonogram. The gestational ages ranged between 20 and 41 weeks. Regressing the umbilical cord diameter (y) on gestational age (x) in a nonlinear polynomial OLS equation produced y = - 11.889 + 1.352x -.01888x 2 and a fit measure of R 2 = 0.172. All variables yielded statistical significance with the intercept term -11.889 yielding P < 0.0001, the coefficient 1.352 on gestation age (x) producing P < 0.0001 and the coefficient of -0.01888 on the squared value of gestational age (x 2 ) generating P < 0.002. The 5 th, 95 th percentile bands as well as the fitted mean values of umbilical cord measures that the regression equation produced are depicted in Figure 3. 10

158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 Discussion The umbilical cord serves an essential role in fetal intrauterine survival, but for a long period of time, it was one of the least studied components of the fetal anatomy during an ultrasound examination [1-2]. Prenatal morphological assessment of the umbilical cord is usually limited to the evaluation of the number of umbilical cord vessels. Other morphometric umbilical cord parameters, such as cord thickness and the amount of Wharton's substance or umbilical cord coiling have been reported but not routinely used [11-12, 22]. Weissman and colleagues conducted the first study constructing nomograms for the umbilical cord components using ultrasound [2]. The authors established reference measures for the diameters of the umbilical cord, vein, and arteries. In a more recent study Raio et al. published nomograms of the umbilical cord diameter and area according to gestational age from 10 to 42 weeks of gestation [1]. In their study, umbilical cords were evaluated at the level of the umbilical cord insertion on 557 patients. They demonstrated an increase in umbilical cord thickness as a function of gestational age up to 34 weeks of gestation, followed by a reduction of this parameter. These findings were similar to the nomogram published by Weissman except the cessation of cord thickness in the latter study 176 was observed later after 36 weeks [2]. 11

177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 We replicated the findings of Raio et al., which are shown in Figure 4 [1]. Based on a sample of 557 patients and gestational age range of 10 weeks to 41 weeks, the Raio et al. study generated y = - 10.0563 + 1.4265x -.0194x 2 with umbilical cord diameter as the dependent variable, y, and gestational age and its square as the explanatory variables (x and x 2 ). In Figure 5, we compare Raio, et al. s findings with ours. As shown, there is considerable similarity between the two results generated with the in vitro direct measurement of the umbilical cord and in vivo measurements obtained by ultrasonography which form the basis of the Raio et al. data [1]. We found a statistically significant non-linear relationship between umbilical cord diameters and gestational age. But the direct measurements of umbilical cords during the pathological examination were smaller than the ultrasound measurements by 30-40% over the gestational age range of 20 to 41 weeks. Although evaluation of the umbilical cord has been part of every recommendation on pathological examination of the placental specimens, reference values for umbilical cord diameters applicable to pathological specimens are not currently available. The sources of the nomograms in the published pathology literature are from ultrasound studies obtained in ongoing pregnancies. Since after delivery the fetal circulation ceases through the umbilical 12

196 197 198 199 200 201 202 203 204 cord, the shape and measurements of this conduit changes. Thus they are not compatible [17-21]. In this study, we determined the reference values for average umbilical cord diameters in placenta specimens and their distribution according to gestational ages. Our nomogram is the first derived from the placental specimens rather than in vivo ultrasound examinations. Since the published reference values of umbilical cord thickness in the pathology literature reflect in vivo ultrasound measurements, they are not appropriate. We recommend the use of the new values during the pathologic examinations. 13

205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 References 1. Raio L, Ghezzi F, Di Naro E, Gomez R, Franchi M, Mazor M and Brühwiler H. Sonographic measurement of the umbilical cord and fetal anthropometric parameters. Eur J Obstet Gynecol Reprod Biol. 1999;83(2):131-5. 2. Weissman A, Jakobi P, Bronshtein M, Goldstein I. Sonographic measurements of the umbilical cord and vessels during normal pregnancies. J Ultrasound Med. 1994;13(1):11-4. 3. Sherer DM, Anyaegbunam A. Prenatal ultrasonographic morphologic assessment of the umbilical cord: a review. Part I. Gynecol Surv. 1997;52(8):506-14. 4. de Laat MW, Franx A, van Alderen ED, Nikkels PG, Visser GH. The umbilical coiling index, a review of the literature. J Matern Fetal Neonatal Med. 2005;17(2):93-100. 5. de Laat MW, Franx A, Bots ML, Visser GH, Nikkels PG. Umbilical coiling index in normal and complicated pregnancies. Obstet Gynecol. 2006;107(5):1049-55. 14

222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 6. de Laat MW, van Alderen ED, Franx A, Visser GH, Bots ML, Nikkels PG. The umbilical coiling index in complicated pregnancy. Eur J Obstet Gynecol Reprod Biol. 2007;130(1):66-72. 7. Predanic M, Perni SC, Chasen S, Chervenak FA. Fetal aneuploidy and umbilical cord thickness measured between 14 and 23 weeks' gestational age. J Ultrasound Med 2004;23(9):1177 83. 8. Predanic M, Perni SC, Chasen ST. The umbilical cord thickness measured at 18-23 weeks of gestational age. J Matern Fetal Neonatal Med. 2005;17(2):111-6. 9. Raio L, Ghezzi F, Di Naro E, Franchi M, Maymon E, Mueller MD, Brühwiler H. Prenatal diagnosis of a lean umbilical cord: a simple marker for the fetus at risk of being small for gestational age at birth. Ultrasound Obstet Gynecol. 1999B;13(3):176-80. 10. Raio L, Ghezzi F, Di Naro E, Duwe DG, Cromi A, Schneider H. Umbilical cord morphologic characteristics and umbilical artery Doppler parameters in intrauterine growth-restricted fetuses. J Ultrasound Med 2003;22:1341 7. 11. Prabhcharan G, Jarjoura D. Wharton s jelly in the umbilical cord. A study of its quantitative variations and clinical correlates. J Reprod Med 1993;38:612 14 15

241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 12. Ghezzi F, Raio L, Di Naro E, Franchi M, Balestredi 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. 13. Raio L, Ghezzi F, Di Naro E, Franchi M, Bolla D, Schneider H. Altered sonographic umbilical cord morphometry in early-onset preeclampsia. Obstet Gynecol 2002;100:311 6. 14. Ghezzi F, Raio L, Di Naro E, Franchi M, Buttarelli M, Schneider H. Firsttrimester umbilical cord diameter: a novel marker of fetal aneuploidy. Ultrasound Obstet Gynecol 2002;19(3):235-9. 15. Cromi A, Ghezzi F, Di Naro E, Siesto G, Bergamini V, Raio L. Large crosssectional area of the umbilical cord as a predictor of fetal macrosomia. Ultrasound Obstet Gynecol. 2007;30(6):861-6. 16. Driscoll SG, Langston C. College of American Pathologists Conference XIX on the Examination of the Placenta: Report of the Working Group on Methods for Placental Examination. Arch Pathol Lab Med 1991;115:704-8. 17. Langston C, Kaplan C, Macpherson T, et al. Practice guideline for examination of the placenta. Developed by the placental pathology practice guideline development task force of the College of American Pathologists. Arch Pathol Lab Med 1997;121:449 76. 16

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269 270 Table 1 Indications of placental examination at Women & Infants Hospital of Rhode Island Placental indications Macroscopic abnormality of the placenta, membranes, or cord noted by U/S or at the delivery Abruptio placenta Retained placenta Suspected small or large placenta Suspected short or long cord (indicate on requisition length of cord that we will not receive) Maternal indications Systemic disorders with clinical concerns for mother or infant Diabetes during any portion of pregnancy Hypertensive disorders Autoimmune disorders Hematologic disorders Seizures Premature delivery Delivery at 42 weeks Oligohydramnios or polyhydramnios Peripartum fever and/or infection Clinical concern for infection during gestation Viruses, including HIV Bacteria, including Mycobacteria Fungi Parasites, etc. Prolonged ( 18 hrs) and/or premature rupture of membranes Heavy or repetitive bleeding other than minor first trimester spotting Abruption Intrauterine invasive procedures with suspected placental, umbilical cord or fetal injury Current known substance abuse or positive drug screen Severe trauma FETAL/NEONATAL INDICATIONS Fetal or perinatal death Fetal or neonatal congenital anomalies, known or suspected Compromised clinical conditions similar but not limited to the following examples: Cord blood ph <7.0 Apgar scores <6 at 5 minutes Ventilatory assistance >10 minutes Anemia - Hct <35% Hydrops fetalis Seizures, persistent hypotonia, and hypoxic-ischemic encephalopathy Infections, known or suspected Intrauterine growth retardation or macrosomia (>4500 g for term infants) Multiple gestation, including vanishing twin 18

271 Prematurity 34 weeks or postmaturity weeks Hematologic disorders as defined by: Anemia of any cause Erythroblastosis of any cause Hemoglobinopathies Thrombocytopenia of any cause 272 19