Umbilical cord diameter percentile curves and their correlation to birth weight and placental pathology

Placenta 34 (2013) 62e66

Contents lists available at SciVerse ScienceDirect

Placenta journal homepage: www.elsevier.com/locate/placenta

Umbilical cord diameter percentile curves and their correlation to birth weight and placental pathology L.K. Proctor a, c, B. Fitzgerald a, W.L. Whittle b, c, N. Mokhtari a, E. Lee a, G. Machin a, c, J.C.P. Kingdom b, c, S.J. Keating a, c, * a b c

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G1X5, Canada Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G1X5, Canada University of Toronto, Toronto M5G 1X8, Canada

a r t i c l e i n f o

a b s t r a c t

Article history: Accepted 26 October 2012

Objective: The aims of this study were to develop a nomogram of umbilical cord diameter (UCD) for pathologic examination of the placenta, to identify the umbilical cord components responsible for variations in UCD, and to examine the relationship between UCD and other placental pathologic features and perinatal outcome. Study design: We prospectively collected 497 umbilical cords between 18 and 41 weeks’ gestation over a 1-year period. Fresh-tissue UCD were grouped according to gestational age and compared to sonographic and histological measurements. Associations between UCD percentile and placental pathologic findings or obstetrical outcomes were examined. Results: Mean UCD increased with gestational age until a plateau at 1.0 cm in the third trimester, a value that was 0.56 cm less than sonographic measurements prior to delivery and 0.17 cm greater than UCD measured histologically. Umbilical cord components varied with UCD percentile, with umbilical vessel area increased in thick cords (p < 0.001) and Wharton’s jelly area reduced in thin cords (p ¼ 0.002). Thin umbilical cords were associated with at least one pathologic histological placental finding (p ¼ 0.02), low placental weight (p < 0.001), single umbilical artery (p ¼ 0.02), marginal cord insertion (p ¼ 0.01), and low infant birth weight (p < 0.001). Conclusions: This study provides reference curves for post-delivery UCD from 18 to 41 weeks’ gestation for use by perinatal pathologists. We show that increased UCD is a function of increased umbilical blood vessel volume and decreased UCD is a function of decreased Wharton’s jelly volume. UCD shows a strong association with placental and infant birth weight. Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.

Keywords: Umbilical cord diameter Percentile curve Nomogram Birth weight Placenta Pathology

1. Introduction The umbilical cord connects the developing fetus to the placenta for nutrient uptake, waste elimination and gas exchange. In humans, two umbilical arteries carry deoxygenated blood from the fetus to the placenta, while oxygenated blood is returned via the larger umbilical vein [1]. These vessels are suspended in an extracellular matrix of Wharton’s jelly, encased within an outer covering of amniotic epithelium, and insert into the fetal surface of the placental disc [1]. The umbilical cord is normally 60 cm in length at Abbreviations: UC, umbilical cord; UCD, post-delivery, fresh-tissue umbilical cord diameter calculated from length and weight. * Corresponding author. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G1X5, Canada. Tel.: þ1 416 586 4800x8748; fax: þ1 416 586 8628. E-mail address: [email protected] (S.J. Keating).

term and helical in shape, with a chirality of 1e3 coils per 10 cm of length [1]. A variety of nomograms for sonographic measurements of umbilical cord diameter (UCD) over gestation have been developed [2e5]. There is mounting evidence that the sonographic characteristics of the umbilical cord may be useful in predicting adverse perinatal outcomes, including fetal aneuploidy, macrosomy, growth restriction, fetal heart rate disturbances, intrauterine demise and preeclampsia [2,6e11]. However, a nomogram of UCD measured following delivery for use by pathologists has not been established but would be a useful tool for the pathologic examination of the placenta. Such a nomogram would increase the amount of information that can be obtained by examining the placenta pathologically and could be of clinical significance. The purpose of this study was to develop post-delivery reference values for UCD across gestational age. In addition to this there

0143-4004/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.placenta.2012.10.015

L.K. Proctor et al. / Placenta 34 (2013) 62e66

were three further aims. The first was to identify the umbilical cord components (vessel and/or Wharton’s jelly) responsible for the change in UCD in thin and thick umbilical cords. The second was to examine the relationship between UCD and other placental pathologic features. The third was to examine the relationship between post-delivery UCD and perinatal outcome. 2. Methods 2.1. Inclusioneexclusion criteria We prospectively collected umbilical cords from women delivering between 15 and 43 weeks of gestation whose placentas were sent to the pathology laboratory at Mount Sinai Hospital (Toronto, Canada) in 2005. Mount Sinai Hospital is a tertiary facility that specializes in high-risk pregnancies, including those with chromosomal or structural anomalies, preeclampsia and pre-term delivery. Our tertiary centre delivers roughly 6500 pregnancies each year, 2000 of which are high-risk. Approximately 1/6 have their placentas sent to pathology based on indications similar to those described by Langston et al. (1997) [12]. Hospital research ethics board approval was obtained. Umbilical cords from all singleton pregnancies with a known gestational age at delivery were incorporated in the study, including pregnancies with chromosomal and structural anomalies. Eight umbilical cords were excluded from the study e one had an unknown gestational age and four had fewer than 3 samples at a gestational age category (two at 15, one at 42 and one at 43 weeks gestation). Because no umbilical cords were collected at 17 weeks gestation, a further three were excluded at 16 weeks gestation for sample continuity when calculating the percentile curves. This left a final sample of 497 umbilical cords for the production of percentile curves from 18 to 41 weeks gestation. Gestational age was determined based on first-trimester measurements of the fetal crownerump length or from biparietal diameter before 16 weeks’ gestation. 2.2. Umbilical cord diameter nomogram Umbilical cord diameter (UCD) was derived in the first 43 samples from the volume of umbilical cord segments in order to get a reliable average diameter. The umbilical cord was removed immediately adjacent to the placental disc the volume was measured by measuring displacement in a graduated cylinder partially filled with water. The weight and length of each segment of fresh-tissue were also measured. Volume was found to be similar to umbilical cord weight following a linear association analysis using the Pearson product moment correlation (p < 0.001; r ¼ 0.997; y ¼ 1.071x  0.644), which allowed for the substitution of weight in place of volume for the calculation of umbilical cord diameter (UCD) in all subsequent samples. UCD ¼ 2  Oðweight=p  lengthÞ

(1)

Fresh-tissue UCDs were grouped according to gestational age (in completed weeks) and the LMS method was applied to smooth the data using a power transformation for the production of percentile curves, as described by Cole (1990) [13e15]. Umbilical cord diameters <10th, between the 10th and 90th, or >90th percentile were classified as “thin”, “average” or “thick”, respectively. Calculated fresh-tissue UCDs were compared to previously published sonographic measurements of UCD over gestation [2]. 2.3. Histological analysis Portions of umbilical cord were fixed in 4% formaldehyde, embedded in paraffin, sectioned at 5 mm and stained with hematoxylin and eosin as per standard placental grossing guidelines. Cord diameters were measured on the slide for 73 cases e 20 thin (<10th percentile), 42 average (10the90th percentile) and 11 thick (>90th percentile). Measurements were taken as follows: two cord diameters from each histological section were measured at right angles to each other and averaged using a microscope and graticule. This was performed on two sections of umbilical cord for each placenta e one from the fetal end and one from the placental end e then averaged. The diameter of each blood vessel cross section was obtained in the same way, but included separate measurements for the entire vessel diameter and that of the lumen only. The average cross-sectional area of the cord, vessels and lumens could then be calculated and the average area of the umbilical cord that was made up of Wharton’s jelly or muscular vessel wall were derived. 2.4. Placenta pathology The placentas were processed and examined using a standard protocol based on the College of American Pathologists guidelines [12]. Sampling and paraffinembedding of umbilical cord, a fetal membrane roll, representative full thickness sections of normal parenchyma and any gross parenchymal lesions were performed, with a minimum of 4 parenchymal sections being submitted in total. Sections from each of these tissue blocks were processed routinely and reviewed (by SK and GM)

63

using pre-determined criteria for ischemic-thrombotic and inflammatory lesions [1,12,16]. Infarction of placental villi was defined as ischemic villous necrosis in (1) any non-peripheral regions of the placenta at <37 weeks’ gestation or (2) involving greater than 5% of placental parenchyma in placentas 37 weeks’ gestation [17]. Decidual vasculopathy was defined as hyaline necrosis of the decidual spiral artery wall and/or acute atherosis [17]. Excess peri-villous fibrinoid was defined as perivillous fibrinoid surrounding more than 25% of the villi in at least one histologic section, with involvement of more than the subchorionic villi. Increased syncytial knots were defined as syncytial knots involving more than one-third of chorionic villi in any given section in placentae <37 weeks gestation. This lesion was not considered pathological in term placentae. For the purposes of this study the term acute chorioamnionitis was used when either stage 2/3 or 3/3 maternal inflammation was present or when there was a fetal inflammatory response. Cord coiling index was calculated by counting the number of coils per 10 cm of cord length: greater than 3 coils and less than 1 was considered to be increased and decreased coiling index respectively [18]. 2.5. Obstetrical outcome Obstetrical data were obtained from the patients’ charts and included: birth weight, Apgar scores at 1 and 5 min of post-natal life and the presence of fetal structural or chromosomal anomalies. Birth weights were categorized into percentile groups according to sex and gestational age [19]. Apgar scores were categorized as “low” or “high” when they were 6 or 7 at 5 min, respectively [11,20]. 2.6. Statistics The strength of linear associations between pairs of variables was measured using the Pearson product moment correlation coefficient and linear regression analysis. This method was used for the comparison of UCD calculated in our study to previously reported mean sonographic UCD at each gestational age [2]. The Chisquare test was used to determine significant associations between UCD percentile and placental pathologic findings or obstetrical outcomes. The Chi-square test was also used to determine significant associations between UCD percentile and obstetrical outcomes, but only in pregnancies delivering 28 weeks’ gestation that did not result in fetal anomalies or intrauterine fetal demise, in order to assess fetal viability. The umbilical cord vessel area and Wharton’s jelly area at different UCD percentiles were compared using a one-way ANOVA, followed by the Tukey’s posthoc test. Statistical calculations were performed using SigmaStat 3.1software (Systat Software, San Jose, CA, USA) and p-values <0.05 were considered significant.

3. Results Table 1 summarizes the fresh-tissue umbilical cord diameter (UCD) percentiles and Fig. 1 illustrates the percentile curves over gestational age. Mean UCD increased with gestational age then plateaued at 1.0 cm from 28 weeks gestation (Fig. 1). Although our measurements of fresh-tissue UCD positively correlated with previously reported mean sonographic measurements of UCD across gestation (p < 0.001; r ¼ 0.578; y ¼ 0.6048x þ 0.07059) [2], the mean sonographic measurements overestimated our freshtissue measurements of UCD on average by 0.41 cm in pregnancies <28 weeks and by 0.56 cm in pregnancies 28 weeks gestation. Fresh-tissue measurements of UCD were also compared to UCDs obtained from histological slide measurements for linear associations using the Pearson product moment correlation. Histological measurements of UCD were positively correlated with fresh-tissue measurements (p < 0.001; r ¼ 0.860). However linear regression analysis suggested that histological measurements tended to underestimate fresh-tissue measurements of UCD (y ¼ 0.6366x þ 0.1858), on average by 0.11 cm in pregnancies <28 weeks and by 0.17 cm in pregnancies 28 weeks. Further histological analysis revealed that the vessel and Wharton’s jelly area of umbilical cords varied depending on UCD percentile. Umbilical vessel area was significantly increased in thick cords compared to average and thin cords (thin, 16.62 mm2  2.53 SEM; average,14.68 mm2  1.92; thick, 39.18 mm2  11.29; p < 0.001, one-way ANOVA; Fig. 2A). This was due to an increase in umbilical artery wall thickness as opposed to dilation of the vessel lumen. Umbilical artery wall area in thick cords was significantly increased compared to average and thin cords (umbilical artery: thin,

L.K. Proctor et al. / Placenta 34 (2013) 62e66

Gestational age Umbilical cord diameter (cm) (completed weeks) 10th 50th 90th n percentile percentile percentile

Mean Standard deviation

18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

0.53 0.51 0.72 0.61 0.69 0.75 0.84 0.86 0.93 0.93 1.04 0.92 1.04 1.06 1.04 1.06 1.03 0.97 1.03 1.02 1.04 1.01 1.04 1.05

0.36 0.43 0.50 0.56 0.62 0.67 0.72 0.77 0.80 0.83 0.85 0.87 0.88 0.88 0.88 0.88 0.87 0.86 0.85 0.84 0.83 0.82 0.81 0.80

0.46 0.54 0.60 0.67 0.72 0.78 0.83 0.87 0.91 0.94 0.97 1.00 1.02 1.03 1.05 1.05 1.06 1.06 1.05 1.05 1.03 1.02 1.00 0.98

0.61 0.68 0.73 0.79 0.84 0.88 0.93 0.97 1.01 1.05 1.09 1.12 1.15 1.18 1.20 1.22 1.23 1.24 1.25 1.24 1.23 1.22 1.19 1.16

4 10 8 9 17 14 18 9 9 7 4 9 16 13 10 16 23 17 33 40 54 58 59 40

0.08 0.12 0.30 0.14 0.09 0.20 0.13 0.12 0.13 0.09 0.06 0.16 0.18 0.16 0.14 0.20 0.24 0.13 0.17 0.14 0.18 0.15 0.14 0.17

4.33 mm2  0.69; average, 4.24 mm2  0.73; thick,13.87 mm2  5.16; p ¼ 0.001; umbilical vein: thin, 6.13 mm2  1.40; average, 2.96 mm2  0.83; thick, 6.15 mm2  3.10; p ¼ 0.13). There was no significant change in lumen area with UCD (umbilical artery: thin, 0.30 mm2  0.16; average, 0.48 mm2  0.26; thick, 0.69 mm2  0.25; p ¼ 0.76; umbilical vein: thin, 1.22 mm2  0.27; average, 2.30 mm2  0.51; thick, 3.90 mm2  1.22; p ¼ 0.06). Wharton’s jelly area was significantly reduced in thin cords compared to average but not thick cords (thin, 16.75 mm2  3.69; average, 36.17 mm2  2.70; thick, 27.42 mm2  8.75; p ¼ 0.002; Fig. 2B). Placental pathologies are summarized in Table 2. The majority (86.7%) of placentas had at least one pathologic finding associated with them. In addition, the proportion of placentas with a pathologic finding was significantly associated with UCD percentile (p ¼ 0.02, Chi-squared test), with thin UCD having a higher proportion of placentas with at least one pathologic finding. Thin umbilical cords were also associated with low placental weight

A 60

Vessel Area (mm2)

Table 1 Umbilical cord diameter percentiles and mean and standard deviation of the cohort (N ¼ 497). UCD was calculated using the formula: UCD ¼ 2  O(weight/p  length). The substitution of weight in place of volume was used after showing that umbilical cord volume was similar to weight (p < 0.001; r ¼ 0.997; y ¼ 1.071x  0.644).

*

40

20

0

Thin Average Thick Umbilical Cord Diameter

B Wharton’s Jelly Area (mm2)

64

60

* 40

20

0

Thin Average Thick Umbilical Cord Diameter Fig. 2. Average vessel (A) and Wharton’s jelly (B) area according to umbilical cord diameter (UCD). Thick UCD had a significantly larger vessel area than average or thin UCD (p < 0.001, one-way ANOVA). Thin UCD had a significantly smaller Wharton’s jelly area than average but not thick UCD (p ¼ 0.002).

percentile (p < 0.001; Table 2 and Fig. 3A), a single umbilical artery (p ¼ 0.02) and marginal umbilical cord insertion (p ¼ 0.01). UCD percentile was not associated with umbilical cord coiling (p ¼ 0.63) or any specific microscopic pathologic findings. The obstetrical outcomes of pregnancies 28 weeks’ gestation, that did not end in intrauterine fetal demise or have any known structural or genetic anomalies, were reviewed to explore the relationship between UCD and fetal viability (Table 3). UCD percentile was significantly associated with birth weight percentile (p < 0.001, Fig. 3B). Forty percent of thin UCD had birth weights <10th percentile, compared to 19% and 2% in the average and thick UCD groups, respectively (Fig. 3B). Twenty percent of thick UCD were associated with placental weights >90th percentile, compared to 9% and 5% in the average and thin UCD groups, respectively (Fig. 3B). UCD was not associated with high (7) or low (6) Apgar scores at 5 min (p ¼ 0.78). 4. Discussion

Fig. 1. Post-delivery, fresh-tissue umbilical cord diameter (UCD) according to gestational age. The lines represent the 10th, 50th and 90th percentile curves.

The umbilical cord is an important component of the placenta. Empirical observations that a thin umbilical cord on ultrasound is associated with poor pregnancy outcome led to this detailed study of UCDs of placentas received in our tertiary care centre laboratory. The present study provides reference curves for post-delivery UCD from 18 to 41 weeks’ gestation. Our cohort was derived from pregnancies delivering within a 1-year period at Mount Sinai Hospital in Toronto, a tertiary care centre that specializes in high-risk pregnancies. This sample is representative of the diverse range of pregnancies delivering at a tertiary centre between 18 and 41 weeks’

L.K. Proctor et al. / Placenta 34 (2013) 62e66

65

Table 2 Placental pathology findings. Total

Placental pathology Any placental pathology Gross pathology Small placentaa Large placentaa Overcoiled UC Undercoiled UC Marginal UC insertionb Single umbilical artery Circummarginate membranes Microscopic pathology Acute chorioamnionitisc Excessive peri-villous fibrinoid Intervillous thrombus Infarction Fetal thrombotic vasculopathy Chronic deciduitis Retroplacental hemorrhage Distal villous hypoplasia Accelerated villous maturation Chronic villitis of unknown etiology Decidual vasculopathy Persistent villous immaturity

N ¼ 497

Umbilical cord diameter (cm) Thin

n ¼ 67

Average

n ¼ 362

Thick

n ¼ 68

Chi-squared p value

n

%

n

%

n

%

n

%

431

86.7

63

94.0

312

86.2

56

82.4

0.02

105 47 177 21 104 22 11

22.6 10.1 35.6 4.2 21.6 4.4 2.2

27 3 29 2 22 8 1

44.3 4.9 43.3 3.0 35.5 11.9 1.5

73 32 126 15 66 14 9

21.5 9.4 34.8 4.1 18.6 3.9 2.5

5 12 22 4 16 0 1

7.7 18.5 32.4 5.9 24.6 0 1.5

<0.001

0.01 0.02 NS

84 60 61 48 36 35 26 22 16 13 12 10

16.9 12.1 12.3 9.7 7.2 7.0 5.2 4.4 3.2 2.6 2.4 2.0

10 13 6 8 8 8 3 3 5 1 3 2

14.9 19.4 9.0 11.9 11.9 11.9 4.5 4.5 7.5 1.5 4.5 3.0

57 39 47 35 24 21 20 18 9 10 8 8

15.7 10.8 13.0 9.7 6.6 5.8 5.5 5.0 2.5 2.8 2.2 2.2

17 8 8 5 4 6 3 1 2 2 1 0

25.0 11.8 11.8 7.4 5.9 8.8 4.4 1.5 2.9 2.9 1.5 0.0

NS NS NS NS NS NS NS NS NS NS NS NS

NS

UC, umbilical cord. a 32 placentas did not have a weight measured. b 15 placentas did not have an umbilical cord insertion assessed. c Acute chorioamnionitis stages 2 or 3.

gestation, including a subset with chromosomal or structural anomalies. We acknowledge that this is a limitation of the study since a low risk population may provide a different nomogram, however it is very difficult to find a population like this in most hospital settings.

A

B

Fig. 3. Graphic representation of the association between umbilical cord diameter percentile and placental weight (A; p < 0.001, Chi-squared) and umbilical cord diameter and birth weight (B; p < 0.001).

We show that UCD increases with gestational age until 28 weeks gestation, when it begins to plateau at approximately 1.0 cm. These findings are in agreement with antenatal ultrasound assessment of UCD that describe an increase in UCD with gestational age until the third trimester [2,21]. Despite this similarity, fresh-tissue measurements of UCD are smaller than the sonographic measurements, differing by a predictable factor [2]. The smaller diameter of our fresh-tissue UCD may be a result of post-delivery cord exsanguination prior to pathological examination and/or post-natal loss of fluid from Wharton’s jelly [22]. The observed difference between sonographic and fresh-tissue nomograms suggests that post-delivery UCD measurements would be of better use by pathologists. In order for the nomogram to be useful in pathology practice, we measured and averaged UCD on glass slides and correlated them with our fresh-tissue measurements. There was a good correlation between measurements, with the average glass slide diameter smaller by 0.11 cm in pregnancies <28 weeks and by 0.17 cm in pregnancies 28 weeks, attributable to shrinkage artifact due to tissue processing. In situations where UCD cannot be calculated from volume displacement or weight because adding these additional steps may not be practical, we suspect that our method of evaluating cord diameter on the slide is more accurate than a single gross measurement of UCD where there may be a tendency to measure the larger diameter of cords that are oval in cross section. Measuring and averaging umbilical cord cross sections on a slide and using a correction factor of 0.11 cm <28 weeks or 0.17 cm 28 weeks is a practical alternative to weighing and can be done in cases where cord diameter might be an issue such as in unexplained intrauterine growth restriction or fetal demise. Using our nomogram we identified thin (<10th percentile), average (10the90th percentile) and thick (>90th percentile) umbilical cords and determined the umbilical cord components responsible for the change in diameter. Our findings show that a significant increase in vessel area, specifically an increase in umbilical artery wall area, is responsible for thick UCD, while a significant decrease in

66

L.K. Proctor et al. / Placenta 34 (2013) 62e66

Table 3 Obstetrical outcomes in pregnancies 28 weeks gestation. Total

Obstetric outcome 28 weeks gestationa Apgar score, 1 minb 8 9 Apgar score, 5 minb 13 Low Apgar scoreb 342 High Apgar scoreb Birth weight (g) (mean  SD) 2871 <10th percentile (n, %) 69 10the90th percentile (n, %) 251 >90th percentile (n, %) 36

N ¼ 356a

(7e9) (9e9) 3.7% 96.1% 786 19.4% 70.5% 10.1%

Umbilical cord diameter (cm) Thin

n ¼ 38

Average

n ¼ 273

Thick

n ¼ 45

p Value

8 9 2 35 2186 15 21 2

(6e9) (8e9) 5.3% 92.1% 689 39.5% 55.3% 5.3%

9 9 9 264 2946 53 195 25

(8e9) (9e9) 3.3% 96.7% 734 19.4% 71.4% 9.2%

9 9 2 43 2989 1 35 9

(7e9) (8e9) 4.4% 95.6% 894 2.2% 77.8% 20.0%

e e NS e <0.001

Values in median (interquartile range) or n (%). a Thirty-five pregnancies 28 weeks gestation were excluded for chromosomal or structural anomalies (30) or intrauterine fetal demise (5). b Apgar score was missing for one patient.

Wharton’s jelly area is responsible for thin UCD. These findings contrast somewhat to that described by Baergen (c2001) who explained that increased UCD was due to an increase in Wharton’s jelly water content [23]. This discrepancy is likely due to the fact that the increase in UCD described by Baergen (c2001) was a result of umbilical cord edema, polyhydramnios, maternal diabetes or fetal hydrops [23], and may be a feature specific to these conditions. In the current study we showed that there was a relationship between UCD and gross placental pathologic features. Thin umbilical cords were associated with low placental weight percentile, a single umbilical artery and marginal umbilical cord insertion. Single umbilical artery and marginal umbilical cord insertion are known to occur together [1] and are consistent with the features of chorionic regression. UCD was also significantly associated with birth weight at delivery, an observation that has also been made using sonographic measurements of UCD [2]. In summary, we have developed reference values for thin, average and thick UCD as a function of gestational age for use by perinatal pathologists in a tertiary centre. We have also shown that increased UCD size is likely a function of increased umbilical vessel diameter and decreased UCD a function of decreased Wharton’s jelly volume. Furthermore, UCD shows a strong association with placental weight and infant birth weight, suggesting that thin UCD may contribute to the spectrum of placental insufficiency leading to fetal growth restriction. Acknowledgments This project was supported by the Departments of Pathology and Laboratory Medicine and Obstetrics and Gynecology (Division of Maternal-Fetal Medicine), Mount Sinai Hospital, Toronto, CANADA. The authors are indebted to the pathologists’ assistants at Mount Sinai Hospital, Toronto e Brian Chow, Sarah James, Oliver Pangan, Megan Thompson and Alan Wolff for weighing the umbilical cords. References [1] Benirschke K, Kaufmann P, Baergen R. Pathology of the human placenta. 5th ed. New York: Springer-Verlag; 2006. [2] Raio L, Ghezzi F, Di Naro E, Gomez R, Franchi M, Mazor M, et al. Sonographic measurement of the umbilical cord and fetal anthropometric parameters. Eur J Obstet Gynecol Reprod Biol 1999 Apr;83(2):131e5. [3] Ghezzi F, Raio L, Di Naro E, Franchi M, Bruhwiler H, D’Addario V, et al. First-trimester sonographic umbilical cord diameter and the growth of the human embryo. Ultrasound Obstet Gynecol 2001 Oct;18(4):348e51.

[4] 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 Aug;18(2):121e5. [5] Predanic M, Perni SC, Chasen ST. The umbilical cord thickness measured at 18e23 weeks of gestational age. J Matern Fetal Neonatal Med 2005 Feb;17(2): 111e6. [6] Weissman A, Jakobi P. Sonographic measurements of the umbilical cord in pregnancies complicated by gestational diabetes. J Ultrasound Med 1997 Oct; 16(10):691e4. [7] 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 Mar;19(3):235e9. [8] Axt-Fliedner R, Schwarze A, Kreiselmaier P, Krapp M, Smrcek J, Diedrich K. Umbilical cord diameter at 11e14 weeks of gestation: relationship to nuchal translucency, ductus venous blood flow and chromosomal defects. Fetal Diagn Ther 2006;21(4):390e5. [9] Cromi A, Ghezzi F, Di Naro E, Siesto G, Bergamini V, Raio L. Large cross-sectional area of the umbilical cord as a predictor of fetal macrosomia. Ultrasound Obstet Gynecol 2007 Nov;30(6):861e6. [10] Di Naro E, Ghezzi F, Raio L, Franchi M, D’Addario V. Umbilical cord morphology and pregnancy outcome. Eur J Obstet Gynecol Reprod Biol 2001 Jun;96(2):150e7. [11] 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 Mar;17(3):224e8. [12] Langston C, Kaplan C, Macpherson T, Manci E, Peevy K, Clark B, 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 May;121(5): 449e76. [13] Cole TJ. The LMS method for constructing normalized growth standards. Eur J Clin Nutr 1990 Jan;44(1):45e60. [14] Almog B, Shehata F, Aljabri S, Levin I, Shalom-Paz E, Shrim A. Placenta weight percentile curves for singleton and twins deliveries. Placenta 2011 Jan;32(1): 58e62. [15] Thompson JM, Irgens LM, Skjaerven R, Rasmussen S. Placenta weight percentile curves for singleton deliveries. BJOG 2007 Jun;114(6):715e20. [16] Redline RW. Placental pathology: a systematic approach with clinical correlations [Review]. Placenta 2008 March;29(Suppl. A):S86e91. [17] Redline RW, Boyd T, Campbell V, Hyde S, Kaplan C, Khong TY, et al. Maternal vascular underperfusion: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004 May-Jun;7(3):237e49. [18] Machin GA, Ackerman J, Gilbert-Barness E. Abnormal umbilical cord coiling is associated with adverse perinatal outcomes. Pediatr Dev Pathol 2000 SepeOct;3(5):462e71. [19] Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 2001 Aug;108(2):E35. [20] American Academy of Pediatrics, Committee on Fetus and Newborn, American College of Obstetricians and Gynecologists, Committee on Obstetric Practice. The Apgar score. Pediatrics 2006 Apr;117(4):1444. [21] Weissman A, Drugan A. Sonographic findings of the umbilical cord: implications for the risk of fetal chromosomal anomalies. Ultrasound Obstet Gynecol 2001 Jun;17(6):536e41. [22] Stevenson RE, Hall JG. Human malformations and related anomalies. 2nd ed. New York: Oxford University Press; 2006. [23] Baergen RN. Manual of pathology of the human placenta. 2nd ed. New York: Springer-Verlag; 2011.