Pediatric and Developmental Pathology 18, 10–16, 2015 DOI: 10.2350/13-10-1390-OA.1 ª 2015 Society for Pediatric Pathology
Umbilical Hypercoiling in 2nd- and 3rdTrimester Intrauterine Fetal Death ANNEMIEK C. DUTMAN
AND
PETER G.J. NIKKELS*
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
Received October 8, 2013; accepted October 25, 2014; published online October 31, 2014.
ABSTRACT Cases of unexplained intrauterine fetal death (IUFD) can be reduced by full placental examination, with or without autopsy. Determination of the umbilical coiling index (UCI) is considered to be a part of full placental examination. Umbilical hypercoiling (UCI above 0.30 coils/cm) is associated with IUFD. In a large retrospective study, we found an incidence of 18% umbilical hypercoiling in IUFD. We explored the association between umbilical hypercoiling and 2nd- and 3rdtrimester IUFD in 77 cases. There was a significant negative correlation between the UCI and gestational age of IUFD (P , 0.001). More severe cases of hypercoiling were observed in the categories of IUFD at a younger age and with a longer duration. Signs of fetal thrombosis were significantly more present in IUFDs with umbilical hypercoiling. An umbilical cord stricture and hypercoiling seem to be significantly more common in IUFD. The severity of hypercoiling was of no influence on the presence or absence of an umbilical cord stricture. Furthermore, there was no significant difference in signs of cardiac failure between the groups of IUFD with and without umbilical hypercoiling. Our findings may be explained by the theory that hypercoiling leads to a disturbed fetal-placental circulation. Therefore, determination of the UCI should be part of the routine placental examination of cases of IUFD. Key words: fetal death, flow, hypercoiling, placenta, umbilical coiling index, umbilical cord
INTRODUCTION By examination of the placenta, separately or in combination with postmortem examination of the fetus, many cases of fetal death can be explained. However, up to 31% of cases of intrauterine fetal death (IUFD) remain unexplained, in spite of full examination of the placenta and fetus [1,2]. Horn and colleagues [3] documented 15.2% unexplained IUFD because of an *Corresponding author, e-mail: [email protected]
unavailable placenta for autopsy. Other reasons were insufficient clinical data or severe maceration. Full placental investigations reduce the proportion of unexplained stillbirths, compared to those without placental examination [4]. Umbilical cord abnormalities are numerous, ranging from false knots, which have no clinical significance, to abnormalities that may lead to fetal death [5]. Abnormal coiling—especially hypercoiling—of the umbilical cord is associated with IUFD [6,7]. Coiling of the umbilical cord arteries is an intrinsic anatomical feature of the umbilical cord and unlike twists or torsion cannot be undone [8]. Hypercoiling was noted earlier in a case report [9] that documented 2 cases of IUFD (stillborn at 35 and 40 weeks of gestation) caused by an extremely large number of coils of the umbilical cord as the only abnormal pathological finding. Three cases of hypercoiling were found in a study of early IUFD [10]. De Laat and colleagues [11] confirmed the association between fetal death and umbilical hypercoiling, next to a placental maturation defect. Little has been written on a possible correlation of a long umbilical cord and preterm IUFD. An excessively long umbilical cord (ELUC), defined as an umbilical cord of a full-term pregnancy with a length of more than 70 cm, showed a non–statistically significant association with fetal death [12]. In a few studies, umbilical cord stricture at the fetal side has been described as a cause of IUFD, with or without hypercoiling [6,10,13,14]. In conclusion, little is known about umbilical cord abnormalities and IUFD. The aim of our study was to explore whether there is an association between umbilical hypercoiling and 2ndand 3rd-trimester IUFD. We hypothesized that severity of umbilical hypercoiling may be negatively correlated to the gestational age of the stillborns. Our hypothesis was based on the paper of Kaplan and colleagues [15]. They developed a computational model for blood flow in the coiled umbilical artery. In this paper it was demonstrated that increased coiling is associated with a higher driving pressure to perfuse the umbilical cord vessels and placenta, with consequently an increased fetal cardiac workload. We compared signs of cardiac failure (hypertrophy
and ventricular dilatation) and signs of fetal thrombosis between groups of unexplained IUFD with or without umbilical hypercoiling. In cases of hypercoiling, the distribution of the umbilical coiling index (UCI) was studied between groups with presence or absence of an umbilical cord stricture and between groups with a long or no long umbilical cord. Furthermore, we studied the presence of an umbilical cord stricture between groups of IUFDs with or without umbilical hypercoiling.
METHODS This retrospective study was conducted from January 1, 2000, to July 1, 2013, at the Department of Pathology of the University Medical Center Utrecht, a tertiary referral center in the Netherlands. All placentas of cases of IUFD were examined, with and without postmortem examination of the fetus. Cases of postpartum-deceased neonates and terminations of pregnancy were excluded. The UCI was part of the routine examination of the placentas and was studied in fresh, unfixed placentas. The UCI was calculated as the number of coils divided by the length of the cord [16]. Using references values from van Dijk and colleagues [17], we defined hypocoiling as less than 0.07 coils/cm and hypercoiling as more than 0.30 coils/cm. Cases of IUFD of the 2nd and 3rd trimester with umbilical hypercoiling in the report (n 5 77) were extracted from a total of 417 2nd- and 3rd-trimester IUFDs. The IUFDs were classified according to the Tulip classification [18]. The gestational age (in weeks) at the time of delivery of the stillborns was based on the last menstrual period or 1st-trimester ultrasound. The duration of the IUFD was determined by the severity of maceration at postmortem examination of the fetus and placenta, based on the data from Genest and colleagues [19–21]. The cases with umbilical hypercoiling were divided into 4 categories of IUFD and defined as (1) up to 1 day, (2) 2– 7 days, (3) 8–14 days, and (4) more than 14 days. The following data were retrieved from the pathology application forms: maternal age at delivery, parity, placental abruption, preterm rupture of membranes, and presence of diabetes or preeclampsia. Data collected about the fetus and placenta included the gender, maturation of the fetus, weight of the fetus, weight of the heart, cardiac ventricular dilatation, chromosomal abnormalities, congenital malformations, twinship, length of the umbilical cord, UCI, umbilical cord stricture at the fetal side, single umbilical artery, fetal thrombosis (FTV), and velamentous cord insertion. Signs of FTV were defined as ‘‘mild’’ (uniformly avascular villi or villous stromal-vascular karyorrhexis [more than 2 foci/5–15 affected villi per slide] 6 fetal vessel lesions) or ‘‘severe’’ (uniformly avascular villi or villous stromalvascular karyorrhexis [more than 2 foci/average of 15 or more affected villi per slide] 6 fetal vessel lesions) [22]. Fetal hearts were defined as hypertrophic when the weight of the heart was above the mean plus 1 standard deviation (SD) [23]. The umbilical cord strictures were
Table 1. Causes of intrauterine fetal death according to the Tulip classification Frequency Congenital anomaly (1) Placenta (2) Placental bed pathology (2.1) Placental pathology (2.2) Umbilical cord complication (2.3) Not otherwise specified (2.4) Infection (4) Other (5) Trauma (5.3) Unknown (6) Total
%
63
15.1
78 47 9 31
18.7 11.3 2.2 7.4
36
8.6
3
0.7
150 417
36.0 100
not documented in all cases and therefore postmortem photos were reviewed (n 5 319). Ninety-eight postmortem photos were not available because the cases were revisions from other hospitals (n 5 17) or former cases from our own institute without photo documentation (n 5 81). Excessively long umbilical cords were defined as those umbilical cords measuring approximately 2 SD above the mean for full-term pregnancies [12]. Umbilical cords from 20 to 42 weeks of gestational age with a length measuring 2 SD above the mean and lengths of gestational ages 14–20 weeks above the 95th percentile were defined as long cords [24,25]. All other umbilical cord lengths were defined as no long cord. Short cords were defined in a similar manner as long cords, with lengths measuring 2 SD below the mean and below the 5th percentile [24,25]. Cases without internal postmortem examination of the fetus resulted in an incomplete data collection. The data were analyzed using IBM SPSS Statistics (IBM, Armonk, NY, USA), version 20. Pearson correlation was used to determine the associations between gestational age and the UCI and between gestational age and the length of the umbilical cord. We used the chisquare, Mann-Whitney, and Kruskal-Wallis tests for statistical comparisons. P values of 0.05 were considered to indicate statistically significant differences.
RESULTS In this study 77 cases of IUFD with umbilical hypercoiling (18%) were extracted from a total of 417 cases of IUFD. The 77 cases of IUFD with hypercoiling were all classified as unknown according to the Tulip classification. The causes of IUFD of all cases (n 5 417) are shown in Table 1. In cases of IUFD without umbilical hypercoiling, the mean gestational age (SD) was 24.7 (8.4) weeks and the mean maternal age (SD) was 31.6 (5.5) years. Baseline and outcome characteristics of the 77 cases of IUFD with umbilical hypercoiling are summarized in Table 2. The mean gestational age (SD) was 22.6 (6.7) weeks and the mean UCI (SD) was 0.73 (0.43) coils/cm.
UMBILICAL HYPERCOILING IN FETAL DEATH
11
Table 2. Baseline and outcome characteristics of intrauterine fetal death with umbilical hypercoiling Characteristics Maternal age (years), n 5 77 Parity Nulliparous Parous Not documented
Mean ± SD or n (%) 33.5 6 4.7 12 (15.6) 48 (62.3) 17 (22.1)
Preeclampsia Diabetes Preterm rupture of membranes Placental abruption Post mortem examination of the fetus Gender of the infant Male Female Not documented
0 3 1 2 64
Maturation of the fetus (weeks), n 5 64 Weight of the fetus (g), n 5 60 Chromosomal abnormalities Not documented
19.8 6 7.1 446.3 6 721.1 4 (5.2) 10 (13.0)
Congenital malformations Not documented
15 (19.5) 13 (16.9)
(3.9) (1.3) (2.6) (83.1)
37 (48.1) 27 (35.1) 13 (16.9)
Twinship 5 (6.5) Single umbilical artery 1 (1.3) Fetal thrombosis 14 (18.2) Velamentous cord insertion 2 (2.6) Length of the umbilical cord (cm), n 5 76 34.9 6 18.8
There was a negative, strong, and significant correlation between the UCI and gestational age at delivery in weeks (r 5 20.515, r2 5 26.5%, P , 0.001) (Fig. 1). A determination coefficient r2 between 25% and 50% means a strong association according to Pearson correlation. A
Figure 1. Scatterplot of the umbilical coiling index (UCI) against gestational age in weeks of cases of 2nd- and 3rdtrimester intrauterine fetal death with hypercoiling. Cases with a UCI more than 1.00 coils/cm are present only under the gestational age of 23 weeks.
12
A.C. DUTMAN AND P.G.J. NIKKELS
Figure 2. Box plots for the umbilical coiling index (UCI) in categories of intrauterine fetal death. IUFD indicates intrauterine fetal death.
similar correlation was found when we corrected the gestational age at time of delivery (in weeks) with the duration of the IUFD. These are estimated gestational ages when the IUFD has occurred (data not shown). Furthermore, we did not find a UCI above 1.00 coils/cm at a gestational age of 23 weeks or more. Four categories of IUFD were defined: (1) up to 1 day, (2) 2–7 days, (3) 8–14 days, and (4) more than 14 days. More severe cases of umbilical hypercoiling were seen in the categories of IUFD with a longer duration (P 5 0.002) (Fig. 2). The umbilical cord stricture was studied from postmortem photos in 319 cases. From these 319 cases, 32 cases were not assessable, mainly because of an umbilical cord removed very close to the fetus. The other 98 cases without photo documentation were revisions from other hospitals (n 5 17) and former cases from our own institute (n 5 81). An umbilical cord stricture was present in 24 of the 235 assessable cases without hypercoiling. In the assessable cases with hypercoiling (n 5 52), 18 cases showed presence of an umbilical cord stricture (Fig. 3). The presence of an umbilical cord stricture in IUFDs with hypercoiling was significantly more common as compared with IUFDs without hypercoiling (P , 0.001). In the cases with hypercoiling, no significant difference of the UCI was found between the presence and absence of an umbilical cord stricture (P 5 0.507). As would be expected there was a strong and significant correlation between the length of the umbilical cord and gestational age at delivery in weeks (r 5 0.594, r2 5 35.3%, P , 0.001; Fig. 4). The mean length of the umbilical cord was in 2nd trimester 34.1 cm (n 5 60) and in 3rd trimester 55.0 cm (n 5 16). There was no significant difference in length distribution across the different categories of IUFD (P 5 0.343). The distribution of the UCI was the same across groups with long or no long cords (P 5 0.217). Sixteen short umbilical cords were present in the group with no long cords. There were only 4 cases of full-term
Figure 3. Cases of fetal death with hypercoiling and presence or absence of an umbilical cord stricture. A. Fetal death at 22 weeks with a striking example of hypercoiling (umbilical coiling index 5 1.80 coils/cm) and without an umbilical cord stricture. B. Fetal death at 24 weeks with an umbilical cord stricture. C. Fetal death at 27 weeks without an umbilical cord stricture. D. Fetal death at 40 weeks with an umbilical cord stricture.
UMBILICAL HYPERCOILING IN FETAL DEATH
13
Figure 4. Scatterplot of the length of the umbilical cord against gestational age in weeks of cases of 2nd- and 3rdtrimester intrauterine fetal death with hypercoiling.
pregnancies (37 weeks) in our cases of IUFD with hypercoiling, and no ELUCs were present in this small group, according to the definition of Baergen and colleagues [12]. There was no significant difference in presence of cardiac hypertrophy or ventricular dilatation between the groups of IUFD with and without umbilical hypercoiling (P 5 0.573; P 5 0.581; Table 3). There were signs of FTV in 18.2% of IUFDs with hypercoiling (Table 2). Cases of IUFD without hypercoiling showed FTV in 2.9% (n 5 10). Fetal thrombosis (mild plus severe) was strongly significantly more common in IUFDs with umbilical hypercoiling (P , 0.001) (Table 4).
DISCUSSION In this study the incidence of umbilical hypercoiling in IUFD was 18%. We have found a negative linear correlation between the UCI and IUFD. Higher UCIs were found at younger gestational ages (Fig. 1). Our study confirms the association between fetal death and umbilical hypercoiling, as was found in previous studies [6,7,11,13]. Furthermore, a UCI of more than 1.00 coils/ cm was only observed in cases less than 23 weeks of gestational age. Higher UCIs were associated with IUFDs at a younger gestational age with more severe maceration; a possible explanation might be that early IUFDs are likely to be detected later. First, in younger pregnancies Table 3.
Signs of cardiac failure in cases of intrauterine fetal death with or without umbilical hypercoiling
Cardiac hypertrophy
Ventricular dilatation
14
mothers experience no fetal movements yet. Secondly, in the Netherlands no structural ultrasound is provided until a gestational age of 20–22 weeks. Therefore, early IUFD can be present longer before detection by ultrasound. Coiling is an intrinsic feature of the umbilical cord, and coils cannot be undone like twists or torsion [8]. Little is known about the effect of abnormal coiling on the umbilical cord blood flow and the mode of fetal death, although a cardiovascular disturbance seems most likely. It could be due to acute or chronic cardiac failure or a disturbed fetal-placental blood flow. In a study by Predanic and colleagues [26] it was shown that increased coiling was associated with increased venous flow and decreased arterial resistance. In another study it was demonstrated that overcoiled cords were associated with a reduced forward venous flow [27]. The arteries coil around the vein and hypercoiling may make the arteries compress the vein, leading to a hampered venous flow from the placenta to the fetus, as was discussed in studies by Nakai and colleagues [28,29]. It was suggested that coiling may be beneficial for venous and arterial flow to a certain point but further increased coiling may be detrimental for blood flow [30]. Kaplan and colleagues [15] developed a computational model of steady blood flow through a coiled structure resembling an umbilical artery. They showed that the driving pressure for a given blood flow rate is increasing as the number of coils in the cord structure increases. The driving pressure decreases when spacing between the coils increases. The total number of coils has no influence on the maximal values of wall shear stress (WSS). However, when the distance between the coils is smaller, the maximal WSS is significantly larger. Kaplan and colleagues simulated a case with hypercoiling (UCI 5 0.66 coils/cm), which may represent cases that may lead to IUFD. This simulation showed a higher inlet pressure to drive the arterial blood flow and significantly larger maximal WSS, which may have an adverse effect on the development of the fetal cardiovascular system. And furthermore, an increased WSS may damage endothelial cells, which may lead to thrombus formation [31]. In comparison with our study, FTV was associated with hypercoiling in cases of IUFD [6,7,13]. We found signs of FTV in 18.2% of the cases with umbilical hypercoiling and in 2.9% in the nonovercoiled cords (Tables 2,4), a comparable percentage (16 of 76 [21%]) to that found by de Laat and colleagues [7]. The presence of FTV in these cases was usually not
No Yes (%) Total No Yes (%) Total
A.C. DUTMAN AND P.G.J. NIKKELS
Without hypercoiling
With hypercoiling
Total
219 9 (3.9) 228 211 20 (8.7) 231
44 1 (2.2) 45 45 3 (6.3) 48
263 10 273 256 23 279
Table 4. Fetal thrombosis (FTV) in cases of intrauterine fetal death with or without umbilical hypercoiling Without hypercoiling FTV Mild Severe Total (%) No FTV Total
9 1 10 (2.9) 330 340
With hypercoiling 7 7 14 (18.2) 63 77
Total 16 8 24 393 417
comprehensive enough to explain the IUFD. Even in the severe cases, loss of placental villi was not above 30% of the total parenchyma. We hypothesized that umbilical hypercoiling may cause an increased fetal cardiac workload and that it reduces both venous and arterial blood flow. Kaplan and colleagues showed that a higher driving pressure for the umbilical arterial blood flow is needed for the same placental perfusion as the coiling index increases. This may lead to a higher fetal cardiac workload and may support one of our findings that higher umbilical hypercoiling is associated with earlier IUFD and this may be due to earlier fetal cardiac overload. However, signs of cardiac failure (i.e., hypertrophy or dilatation) were not significantly more present in cases of IUFD with umbilical hypercoiling. However, it is not known if the very young fetal heart responds in a similar manner as an adult heart to an increase in workload. The fetal myocardial cells are not the same as adult myocardial cells; the presence and distribution of cell junctions changes during development [32,33]. Myocardial passive stiffness decreases with development of the fetus. In other terms, myocardial compliance increases with development [34]. Maybe the fetal heart responds in a different way to cardiac overload. The association between umbilical hypercoiling and thrombosis may be explained by the larger values of WSS, possible damage of the endothelium, and stasis of the blood flow. Furthermore, a reduction in the venous blood flow due to umbilical hypercoiling may result in hypoxemia in the fetus. In conclusion, it is suggested that umbilical hypercoiling is associated with a disturbance in the fetal-placental circulation and may cause IUFD. Umbilical cord stricture and hypercoiling as a cause of IUFD has been described in a few studies [6,13]. Several case reports have been published on fetal death resulting from umbilical cord stricture, mainly caused by loss of Wharton jelly and replacement by fibrosis [10,14,35]. Stricture of the umbilical cord may be associated with torsion [10,35]. In one case report of IUFD it was suggested that hypercoiling of the umbilical cord led to torsion without a stricture or abnormality of the Wharton jelly [9]. In fetal death, umbilical hypercoiling was reported with or without a stricture [6,10,13]. Peng and colleagues [13] found 19% (26 of 139) of fetal
death cases to have umbilical cord stricture, hypercoiling, or a combination of both. Of those cases, 54% (14 of 26) had an umbilical cord stricture with hypercoiling. According to a similar calculation, our cases (in total 287 assessable cases: 52 with hypercoiling and 235 without hypercoiling) showed an umbilical cord stricture with hypercoiling in 24% (18 of 76; stricture with hypercoiling n 5 18, only stricture n 5 24, only hypercoiling n 5 34). Furthermore, Peng and colleagues reported an incidence of 14% umbilical cord stricture with or without hypercoiling in cases of fetal death. We showed a similar incidence of 15% (42 of 287) umbilical cord stricture in our assessable cases with or without hypercoiling. According to our study, an umbilical cord stricture and hypercoiling seem to be significantly more common in fetal death. The IUFDs with hypercoiling showed an umbilical cord stricture in 35% of cases [18 of 52]. Machin and colleagues [6] reported an incidence of 13% of fetal death associated with umbilical cord stricture in the presence of hypercoiling. We found that severity of hypercoiling was of no influence on the presence or absence of an umbilical cord stricture. As expected, we found a highly significant correlation between the length of the umbilical cord and gestational age at the time of delivery in weeks. A variety of authors found cord lengths to grow linearly. As was suggested by Leonardo da Vinci, the umbilical cord at any gestational age has usually the same length as the fetus [5]. In our study, no definite conclusion could be made about the association between UCI and cord length. The umbilical cord was not always submitted completely to pathology and therefore there is uncertainty about the total length of the umbilical cord. Maybe ‘‘short cords’’ were not short and perhaps there were ELUCs present in our study group. In cases of IUFD with hypercoiling, there were 46 cases with an umbilical cord defined as no long cord (including 16 short cords) and 30 cases with an umbilical cord defined as a long cord. There was no significant difference in the distribution of the UCI between these 2 groups. Also, there were no significant differences in length of the umbilical cord between the 4 categories of IUFD. Excessively long umbilical cords have an association with fetal death [12]. We found no ELUCs in our small group of full-term IUFDs with umbilical hypercoiling. Excessively long umbilical cords were defined as those umbilical cords measuring approximately 2 SD above the mean for full-term pregnancies. In summary, we found a negative correlation between UCI and gestational age. A higher UCI was associated with an IUFD at younger age. We hypothesized that umbilical hypercoiling leads to a reduction of umbilical cord blood flow and increased fetal cardiac workload. Consequently, umbilical hypercoiling may be associated with a disturbance of the fetal-placental circulation and this may be a possible explanation for IUFD. If hypercoiling is accepted as cause of death in the Tulip classification the ‘‘unknown’’ group decreases from 36% to 17.5% and the ‘‘umbilical cord complication’’ group increases from 2.2% to 20.6%. Therefore we recommend
UMBILICAL HYPERCOILING IN FETAL DEATH
15
that determination of the UCI should be part of the routine examination of the placentas of cases of IUFD. REFERENCES 1. Huang DY, Usher RH, Kramer MS, Yang H, Morin L, Fretts RC. Determinants of unexplained antepartum fetal deaths. Obstet Gynecol 2000;95:215–221. 2. Incerpi MH, Miller DA, Samadi R, Settlage RH, Goodwin TM. Stillbirth evaluation: what tests are needed? Am J Obstet Gynecol 1998;178:1121–1125. 3. Horn LC, Langner A, Stiehl P, Wittekind C, Faber R. Identification of the causes of intrauterine death during 310 consecutive autopsies. Eur J Obstet Gynecol Reprod Biol 2004;113:134–138. 4. Heazell AE, Martindale EA. Can post-mortem examination of the placenta help determine the cause of stillbirth? J Obstet Gynaecol 2009;29:225–228. 5. Benirschke K, Burton GJ, Baergen RN. Pathology of the Human Placenta, 6th ed. Berlin, Heidelberg: Springer-Verlag; 2012. 6. Machin GA, Ackerman J, Gilbert-Barness E. Abnormal umbilical cord coiling is associated with adverse perinatal outcomes. Pediatr Dev Pathol 2000;3:462–471. 7. 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;130:66–72. 8. Roach MR. The umbilical vessels. In: Perinatal Medicine, 13th ed. Hagerstown, MD: Harper and Row; 1976:134–142. 9. Herman A, Zabow P, Segal M, Ron-el R, Bukovsky Y, Caspi E. Extremely large number of twists of the umbilical cord causing torsion and intrauterine fetal death. Int J Gynaecol Obstet 1991;35:165–167. 10. Singh V, Khanum S, Singh M. Umbilical cord lesions in early intrauterine fetal demise. Arch Pathol Lab Med 2003;127:850–853. 11. de Laat MW, van der Meij JJ, Visser GH, Franx A, Nikkels PG. Hypercoiling of the umbilical cord and placental maturation defect: associated pathology? Pediatr Dev Pathol 2007;10:293–299. 12. Baergen RN, Malicki D, Behling C, Benirschke K. Morbidity, mortality, and placental pathology in excessively long umbilical cords: retrospective study. Pediatr Dev Pathol 2001;4:144–153. 13. Peng HQ, Levitin-Smith M, Rochelson B, Kahn E. Umbilical cord stricture and overcoiling are common causes of fetal demise. Pediatr Dev Pathol 2006;9:14–19. 14. French AE, Gregg VH, Newberry Y, Parsons T. Umbilical cord stricture: a cause of recurrent fetal death. Obstet Gynecol 2005;105: 1235–1239. 15. Kaplan AD, Jaffa AJ, Timor IE, Elad D. Hemodynamic analysis of arterial blood flow in the coiled umbilical cord. Reprod Sci 2010;17: 258–268. 16. Strong TH Jr, Jarles DL, Vega JS, Feldman DB. The umbilical coiling index. Am J Obstet Gynecol 1994;170:29–32. 17. van Dijk CC, Franx A, de Laat MW, Bruinse HW, Visser GH, Nikkels PG. The umbilical coiling index in normal pregnancy. J Matern Fetal Neonatal Med 2002;11:280–283. 18. Korteweg FJ, Gordijn SJ, Timmer A, et al. The Tulip classification of perinatal mortality: introduction and multidisciplinary inter-rater agreement. BJOG 2006;113:393–401.
16
A.C. DUTMAN AND P.G.J. NIKKELS
19. Genest DR, Singer DB. Estimating the time of death in stillborn fetuses: III. External fetal examination; a study of 86 stillborns. Obstet Gynecol 1992;80:593–600. 20. Genest DR. Estimating the time of death in stillborn fetuses: II. Histologic evaluation of the placenta; a study of 71 stillborns. Obstet Gynecol 1992;80:585–592. 21. Genest DR, Williams MA, Greene MF. Estimating the time of death in stillborn fetuses: I. Histologic evaluation of fetal organs; an autopsy study of 150 stillborns. Obstet Gynecol 1992;80: 575–584. 22. Redline RW, Ariel I, Baergen RN, et al. Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004;7:443–452. 23. Maroun LL, Graem N. Autopsy standards of body parameters and fresh organ weights in nonmacerated and macerated human fetuses. Pediatr Dev Pathol 2005;8:204–217. 24. Naeye RL. Umbilical cord length: clinical significance. J Pediatr 1985;107:278–281. 25. Frederick T. Kraus RWR, Gersell DJ, Nelson DM, Dicke JM. Placental Pathology, 1st ed. King DW, ed. Washington, DC: American Registry of Pathology, Armed Forces Institute of Pathology; 2004. 26. Predanic M, Perni SC, Chervenak FA. Antenatal umbilical coiling index and Doppler flow characteristics. Ultrasound Obstet Gynecol 2006;28:699–703. 27. Clerici G, Antonelli C, Rizzo G, Kanninen TT, Di Renzo GC. Atypical hemodynamic pattern in fetuses with hypercoiled umbilical cord and growth restriction. J Matern Fetal Neonatal Med 2013;26: 558–562. 28. Nakai Y, Imanaka M, Nishio J, Ogita S. Umbilical venous pulsation and regional circulatory disturbance. Ultrasound Med Biol 1997;23: 1165–1169. 29. Nakai Y, Imanaka M, Nishio J, Ogita S. Umbilical venous pulsation associated with hypercoiled cord in growth-retarded fetuses. Gynecol Obstet Invest 1997;43:64–67. 30. Sebire NJ. Pathophysiological significance of abnormal umbilical cord coiling index. Ultrasound Obstet Gynecol 2007;30:804–806. 31. Maalej N, Holden JE, Folts JD. Effect of shear stress on acute platelet thrombus formation in canine stenosed carotid arteries: an in vivo quantitative study. J Thromb Thrombolysis 1998;5: 231–238. 32. Vreeker A, van Stuijvenberg L, Hund TJ, Mohler PJ, Nikkels PG, van Veen TA. Assembly of the cardiac intercalated disk during preand postnatal development of the human heart. PLoS One 2014;9: e94722. 33. Angst BD, Khan LU, Severs NJ, et al. Dissociated spatial patterning of gap junctions and cell adhesion junctions during postnatal differentiation of ventricular myocardium. Circ Res 1997;80:88–94. 34. Friedman WF. The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 1972;15:87–111. 35. Bakotic BW, Boyd T, Poppiti R, Pflueger S. Recurrent umbilical cord torsion leading to fetal death in 3 subsequent pregnancies: a case report and review of the literature. Arch Pathol Lab Med 2000; 124:1352–1355.
Umbilical Hypercoiling in 2nd- and 3rdTrimester Intrauterine Fetal Death ANNEMIEK C. DUTMAN
AND
PETER G.J. NIKKELS*
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
Received October 8, 2013; accepted October 25, 2014; published online October 31, 2014.
ABSTRACT Cases of unexplained intrauterine fetal death (IUFD) can be reduced by full placental examination, with or without autopsy. Determination of the umbilical coiling index (UCI) is considered to be a part of full placental examination. Umbilical hypercoiling (UCI above 0.30 coils/cm) is associated with IUFD. In a large retrospective study, we found an incidence of 18% umbilical hypercoiling in IUFD. We explored the association between umbilical hypercoiling and 2nd- and 3rdtrimester IUFD in 77 cases. There was a significant negative correlation between the UCI and gestational age of IUFD (P , 0.001). More severe cases of hypercoiling were observed in the categories of IUFD at a younger age and with a longer duration. Signs of fetal thrombosis were significantly more present in IUFDs with umbilical hypercoiling. An umbilical cord stricture and hypercoiling seem to be significantly more common in IUFD. The severity of hypercoiling was of no influence on the presence or absence of an umbilical cord stricture. Furthermore, there was no significant difference in signs of cardiac failure between the groups of IUFD with and without umbilical hypercoiling. Our findings may be explained by the theory that hypercoiling leads to a disturbed fetal-placental circulation. Therefore, determination of the UCI should be part of the routine placental examination of cases of IUFD. Key words: fetal death, flow, hypercoiling, placenta, umbilical coiling index, umbilical cord
INTRODUCTION By examination of the placenta, separately or in combination with postmortem examination of the fetus, many cases of fetal death can be explained. However, up to 31% of cases of intrauterine fetal death (IUFD) remain unexplained, in spite of full examination of the placenta and fetus [1,2]. Horn and colleagues [3] documented 15.2% unexplained IUFD because of an *Corresponding author, e-mail: [email protected]
unavailable placenta for autopsy. Other reasons were insufficient clinical data or severe maceration. Full placental investigations reduce the proportion of unexplained stillbirths, compared to those without placental examination [4]. Umbilical cord abnormalities are numerous, ranging from false knots, which have no clinical significance, to abnormalities that may lead to fetal death [5]. Abnormal coiling—especially hypercoiling—of the umbilical cord is associated with IUFD [6,7]. Coiling of the umbilical cord arteries is an intrinsic anatomical feature of the umbilical cord and unlike twists or torsion cannot be undone [8]. Hypercoiling was noted earlier in a case report [9] that documented 2 cases of IUFD (stillborn at 35 and 40 weeks of gestation) caused by an extremely large number of coils of the umbilical cord as the only abnormal pathological finding. Three cases of hypercoiling were found in a study of early IUFD [10]. De Laat and colleagues [11] confirmed the association between fetal death and umbilical hypercoiling, next to a placental maturation defect. Little has been written on a possible correlation of a long umbilical cord and preterm IUFD. An excessively long umbilical cord (ELUC), defined as an umbilical cord of a full-term pregnancy with a length of more than 70 cm, showed a non–statistically significant association with fetal death [12]. In a few studies, umbilical cord stricture at the fetal side has been described as a cause of IUFD, with or without hypercoiling [6,10,13,14]. In conclusion, little is known about umbilical cord abnormalities and IUFD. The aim of our study was to explore whether there is an association between umbilical hypercoiling and 2ndand 3rd-trimester IUFD. We hypothesized that severity of umbilical hypercoiling may be negatively correlated to the gestational age of the stillborns. Our hypothesis was based on the paper of Kaplan and colleagues [15]. They developed a computational model for blood flow in the coiled umbilical artery. In this paper it was demonstrated that increased coiling is associated with a higher driving pressure to perfuse the umbilical cord vessels and placenta, with consequently an increased fetal cardiac workload. We compared signs of cardiac failure (hypertrophy
and ventricular dilatation) and signs of fetal thrombosis between groups of unexplained IUFD with or without umbilical hypercoiling. In cases of hypercoiling, the distribution of the umbilical coiling index (UCI) was studied between groups with presence or absence of an umbilical cord stricture and between groups with a long or no long umbilical cord. Furthermore, we studied the presence of an umbilical cord stricture between groups of IUFDs with or without umbilical hypercoiling.
METHODS This retrospective study was conducted from January 1, 2000, to July 1, 2013, at the Department of Pathology of the University Medical Center Utrecht, a tertiary referral center in the Netherlands. All placentas of cases of IUFD were examined, with and without postmortem examination of the fetus. Cases of postpartum-deceased neonates and terminations of pregnancy were excluded. The UCI was part of the routine examination of the placentas and was studied in fresh, unfixed placentas. The UCI was calculated as the number of coils divided by the length of the cord [16]. Using references values from van Dijk and colleagues [17], we defined hypocoiling as less than 0.07 coils/cm and hypercoiling as more than 0.30 coils/cm. Cases of IUFD of the 2nd and 3rd trimester with umbilical hypercoiling in the report (n 5 77) were extracted from a total of 417 2nd- and 3rd-trimester IUFDs. The IUFDs were classified according to the Tulip classification [18]. The gestational age (in weeks) at the time of delivery of the stillborns was based on the last menstrual period or 1st-trimester ultrasound. The duration of the IUFD was determined by the severity of maceration at postmortem examination of the fetus and placenta, based on the data from Genest and colleagues [19–21]. The cases with umbilical hypercoiling were divided into 4 categories of IUFD and defined as (1) up to 1 day, (2) 2– 7 days, (3) 8–14 days, and (4) more than 14 days. The following data were retrieved from the pathology application forms: maternal age at delivery, parity, placental abruption, preterm rupture of membranes, and presence of diabetes or preeclampsia. Data collected about the fetus and placenta included the gender, maturation of the fetus, weight of the fetus, weight of the heart, cardiac ventricular dilatation, chromosomal abnormalities, congenital malformations, twinship, length of the umbilical cord, UCI, umbilical cord stricture at the fetal side, single umbilical artery, fetal thrombosis (FTV), and velamentous cord insertion. Signs of FTV were defined as ‘‘mild’’ (uniformly avascular villi or villous stromal-vascular karyorrhexis [more than 2 foci/5–15 affected villi per slide] 6 fetal vessel lesions) or ‘‘severe’’ (uniformly avascular villi or villous stromalvascular karyorrhexis [more than 2 foci/average of 15 or more affected villi per slide] 6 fetal vessel lesions) [22]. Fetal hearts were defined as hypertrophic when the weight of the heart was above the mean plus 1 standard deviation (SD) [23]. The umbilical cord strictures were
Table 1. Causes of intrauterine fetal death according to the Tulip classification Frequency Congenital anomaly (1) Placenta (2) Placental bed pathology (2.1) Placental pathology (2.2) Umbilical cord complication (2.3) Not otherwise specified (2.4) Infection (4) Other (5) Trauma (5.3) Unknown (6) Total
%
63
15.1
78 47 9 31
18.7 11.3 2.2 7.4
36
8.6
3
0.7
150 417
36.0 100
not documented in all cases and therefore postmortem photos were reviewed (n 5 319). Ninety-eight postmortem photos were not available because the cases were revisions from other hospitals (n 5 17) or former cases from our own institute without photo documentation (n 5 81). Excessively long umbilical cords were defined as those umbilical cords measuring approximately 2 SD above the mean for full-term pregnancies [12]. Umbilical cords from 20 to 42 weeks of gestational age with a length measuring 2 SD above the mean and lengths of gestational ages 14–20 weeks above the 95th percentile were defined as long cords [24,25]. All other umbilical cord lengths were defined as no long cord. Short cords were defined in a similar manner as long cords, with lengths measuring 2 SD below the mean and below the 5th percentile [24,25]. Cases without internal postmortem examination of the fetus resulted in an incomplete data collection. The data were analyzed using IBM SPSS Statistics (IBM, Armonk, NY, USA), version 20. Pearson correlation was used to determine the associations between gestational age and the UCI and between gestational age and the length of the umbilical cord. We used the chisquare, Mann-Whitney, and Kruskal-Wallis tests for statistical comparisons. P values of 0.05 were considered to indicate statistically significant differences.
RESULTS In this study 77 cases of IUFD with umbilical hypercoiling (18%) were extracted from a total of 417 cases of IUFD. The 77 cases of IUFD with hypercoiling were all classified as unknown according to the Tulip classification. The causes of IUFD of all cases (n 5 417) are shown in Table 1. In cases of IUFD without umbilical hypercoiling, the mean gestational age (SD) was 24.7 (8.4) weeks and the mean maternal age (SD) was 31.6 (5.5) years. Baseline and outcome characteristics of the 77 cases of IUFD with umbilical hypercoiling are summarized in Table 2. The mean gestational age (SD) was 22.6 (6.7) weeks and the mean UCI (SD) was 0.73 (0.43) coils/cm.
UMBILICAL HYPERCOILING IN FETAL DEATH
11
Table 2. Baseline and outcome characteristics of intrauterine fetal death with umbilical hypercoiling Characteristics Maternal age (years), n 5 77 Parity Nulliparous Parous Not documented
Mean ± SD or n (%) 33.5 6 4.7 12 (15.6) 48 (62.3) 17 (22.1)
Preeclampsia Diabetes Preterm rupture of membranes Placental abruption Post mortem examination of the fetus Gender of the infant Male Female Not documented
0 3 1 2 64
Maturation of the fetus (weeks), n 5 64 Weight of the fetus (g), n 5 60 Chromosomal abnormalities Not documented
19.8 6 7.1 446.3 6 721.1 4 (5.2) 10 (13.0)
Congenital malformations Not documented
15 (19.5) 13 (16.9)
(3.9) (1.3) (2.6) (83.1)
37 (48.1) 27 (35.1) 13 (16.9)
Twinship 5 (6.5) Single umbilical artery 1 (1.3) Fetal thrombosis 14 (18.2) Velamentous cord insertion 2 (2.6) Length of the umbilical cord (cm), n 5 76 34.9 6 18.8
There was a negative, strong, and significant correlation between the UCI and gestational age at delivery in weeks (r 5 20.515, r2 5 26.5%, P , 0.001) (Fig. 1). A determination coefficient r2 between 25% and 50% means a strong association according to Pearson correlation. A
Figure 1. Scatterplot of the umbilical coiling index (UCI) against gestational age in weeks of cases of 2nd- and 3rdtrimester intrauterine fetal death with hypercoiling. Cases with a UCI more than 1.00 coils/cm are present only under the gestational age of 23 weeks.
12
A.C. DUTMAN AND P.G.J. NIKKELS
Figure 2. Box plots for the umbilical coiling index (UCI) in categories of intrauterine fetal death. IUFD indicates intrauterine fetal death.
similar correlation was found when we corrected the gestational age at time of delivery (in weeks) with the duration of the IUFD. These are estimated gestational ages when the IUFD has occurred (data not shown). Furthermore, we did not find a UCI above 1.00 coils/cm at a gestational age of 23 weeks or more. Four categories of IUFD were defined: (1) up to 1 day, (2) 2–7 days, (3) 8–14 days, and (4) more than 14 days. More severe cases of umbilical hypercoiling were seen in the categories of IUFD with a longer duration (P 5 0.002) (Fig. 2). The umbilical cord stricture was studied from postmortem photos in 319 cases. From these 319 cases, 32 cases were not assessable, mainly because of an umbilical cord removed very close to the fetus. The other 98 cases without photo documentation were revisions from other hospitals (n 5 17) and former cases from our own institute (n 5 81). An umbilical cord stricture was present in 24 of the 235 assessable cases without hypercoiling. In the assessable cases with hypercoiling (n 5 52), 18 cases showed presence of an umbilical cord stricture (Fig. 3). The presence of an umbilical cord stricture in IUFDs with hypercoiling was significantly more common as compared with IUFDs without hypercoiling (P , 0.001). In the cases with hypercoiling, no significant difference of the UCI was found between the presence and absence of an umbilical cord stricture (P 5 0.507). As would be expected there was a strong and significant correlation between the length of the umbilical cord and gestational age at delivery in weeks (r 5 0.594, r2 5 35.3%, P , 0.001; Fig. 4). The mean length of the umbilical cord was in 2nd trimester 34.1 cm (n 5 60) and in 3rd trimester 55.0 cm (n 5 16). There was no significant difference in length distribution across the different categories of IUFD (P 5 0.343). The distribution of the UCI was the same across groups with long or no long cords (P 5 0.217). Sixteen short umbilical cords were present in the group with no long cords. There were only 4 cases of full-term
Figure 3. Cases of fetal death with hypercoiling and presence or absence of an umbilical cord stricture. A. Fetal death at 22 weeks with a striking example of hypercoiling (umbilical coiling index 5 1.80 coils/cm) and without an umbilical cord stricture. B. Fetal death at 24 weeks with an umbilical cord stricture. C. Fetal death at 27 weeks without an umbilical cord stricture. D. Fetal death at 40 weeks with an umbilical cord stricture.
UMBILICAL HYPERCOILING IN FETAL DEATH
13
Figure 4. Scatterplot of the length of the umbilical cord against gestational age in weeks of cases of 2nd- and 3rdtrimester intrauterine fetal death with hypercoiling.
pregnancies (37 weeks) in our cases of IUFD with hypercoiling, and no ELUCs were present in this small group, according to the definition of Baergen and colleagues [12]. There was no significant difference in presence of cardiac hypertrophy or ventricular dilatation between the groups of IUFD with and without umbilical hypercoiling (P 5 0.573; P 5 0.581; Table 3). There were signs of FTV in 18.2% of IUFDs with hypercoiling (Table 2). Cases of IUFD without hypercoiling showed FTV in 2.9% (n 5 10). Fetal thrombosis (mild plus severe) was strongly significantly more common in IUFDs with umbilical hypercoiling (P , 0.001) (Table 4).
DISCUSSION In this study the incidence of umbilical hypercoiling in IUFD was 18%. We have found a negative linear correlation between the UCI and IUFD. Higher UCIs were found at younger gestational ages (Fig. 1). Our study confirms the association between fetal death and umbilical hypercoiling, as was found in previous studies [6,7,11,13]. Furthermore, a UCI of more than 1.00 coils/ cm was only observed in cases less than 23 weeks of gestational age. Higher UCIs were associated with IUFDs at a younger gestational age with more severe maceration; a possible explanation might be that early IUFDs are likely to be detected later. First, in younger pregnancies Table 3.
Signs of cardiac failure in cases of intrauterine fetal death with or without umbilical hypercoiling
Cardiac hypertrophy
Ventricular dilatation
14
mothers experience no fetal movements yet. Secondly, in the Netherlands no structural ultrasound is provided until a gestational age of 20–22 weeks. Therefore, early IUFD can be present longer before detection by ultrasound. Coiling is an intrinsic feature of the umbilical cord, and coils cannot be undone like twists or torsion [8]. Little is known about the effect of abnormal coiling on the umbilical cord blood flow and the mode of fetal death, although a cardiovascular disturbance seems most likely. It could be due to acute or chronic cardiac failure or a disturbed fetal-placental blood flow. In a study by Predanic and colleagues [26] it was shown that increased coiling was associated with increased venous flow and decreased arterial resistance. In another study it was demonstrated that overcoiled cords were associated with a reduced forward venous flow [27]. The arteries coil around the vein and hypercoiling may make the arteries compress the vein, leading to a hampered venous flow from the placenta to the fetus, as was discussed in studies by Nakai and colleagues [28,29]. It was suggested that coiling may be beneficial for venous and arterial flow to a certain point but further increased coiling may be detrimental for blood flow [30]. Kaplan and colleagues [15] developed a computational model of steady blood flow through a coiled structure resembling an umbilical artery. They showed that the driving pressure for a given blood flow rate is increasing as the number of coils in the cord structure increases. The driving pressure decreases when spacing between the coils increases. The total number of coils has no influence on the maximal values of wall shear stress (WSS). However, when the distance between the coils is smaller, the maximal WSS is significantly larger. Kaplan and colleagues simulated a case with hypercoiling (UCI 5 0.66 coils/cm), which may represent cases that may lead to IUFD. This simulation showed a higher inlet pressure to drive the arterial blood flow and significantly larger maximal WSS, which may have an adverse effect on the development of the fetal cardiovascular system. And furthermore, an increased WSS may damage endothelial cells, which may lead to thrombus formation [31]. In comparison with our study, FTV was associated with hypercoiling in cases of IUFD [6,7,13]. We found signs of FTV in 18.2% of the cases with umbilical hypercoiling and in 2.9% in the nonovercoiled cords (Tables 2,4), a comparable percentage (16 of 76 [21%]) to that found by de Laat and colleagues [7]. The presence of FTV in these cases was usually not
No Yes (%) Total No Yes (%) Total
A.C. DUTMAN AND P.G.J. NIKKELS
Without hypercoiling
With hypercoiling
Total
219 9 (3.9) 228 211 20 (8.7) 231
44 1 (2.2) 45 45 3 (6.3) 48
263 10 273 256 23 279
Table 4. Fetal thrombosis (FTV) in cases of intrauterine fetal death with or without umbilical hypercoiling Without hypercoiling FTV Mild Severe Total (%) No FTV Total
9 1 10 (2.9) 330 340
With hypercoiling 7 7 14 (18.2) 63 77
Total 16 8 24 393 417
comprehensive enough to explain the IUFD. Even in the severe cases, loss of placental villi was not above 30% of the total parenchyma. We hypothesized that umbilical hypercoiling may cause an increased fetal cardiac workload and that it reduces both venous and arterial blood flow. Kaplan and colleagues showed that a higher driving pressure for the umbilical arterial blood flow is needed for the same placental perfusion as the coiling index increases. This may lead to a higher fetal cardiac workload and may support one of our findings that higher umbilical hypercoiling is associated with earlier IUFD and this may be due to earlier fetal cardiac overload. However, signs of cardiac failure (i.e., hypertrophy or dilatation) were not significantly more present in cases of IUFD with umbilical hypercoiling. However, it is not known if the very young fetal heart responds in a similar manner as an adult heart to an increase in workload. The fetal myocardial cells are not the same as adult myocardial cells; the presence and distribution of cell junctions changes during development [32,33]. Myocardial passive stiffness decreases with development of the fetus. In other terms, myocardial compliance increases with development [34]. Maybe the fetal heart responds in a different way to cardiac overload. The association between umbilical hypercoiling and thrombosis may be explained by the larger values of WSS, possible damage of the endothelium, and stasis of the blood flow. Furthermore, a reduction in the venous blood flow due to umbilical hypercoiling may result in hypoxemia in the fetus. In conclusion, it is suggested that umbilical hypercoiling is associated with a disturbance in the fetal-placental circulation and may cause IUFD. Umbilical cord stricture and hypercoiling as a cause of IUFD has been described in a few studies [6,13]. Several case reports have been published on fetal death resulting from umbilical cord stricture, mainly caused by loss of Wharton jelly and replacement by fibrosis [10,14,35]. Stricture of the umbilical cord may be associated with torsion [10,35]. In one case report of IUFD it was suggested that hypercoiling of the umbilical cord led to torsion without a stricture or abnormality of the Wharton jelly [9]. In fetal death, umbilical hypercoiling was reported with or without a stricture [6,10,13]. Peng and colleagues [13] found 19% (26 of 139) of fetal
death cases to have umbilical cord stricture, hypercoiling, or a combination of both. Of those cases, 54% (14 of 26) had an umbilical cord stricture with hypercoiling. According to a similar calculation, our cases (in total 287 assessable cases: 52 with hypercoiling and 235 without hypercoiling) showed an umbilical cord stricture with hypercoiling in 24% (18 of 76; stricture with hypercoiling n 5 18, only stricture n 5 24, only hypercoiling n 5 34). Furthermore, Peng and colleagues reported an incidence of 14% umbilical cord stricture with or without hypercoiling in cases of fetal death. We showed a similar incidence of 15% (42 of 287) umbilical cord stricture in our assessable cases with or without hypercoiling. According to our study, an umbilical cord stricture and hypercoiling seem to be significantly more common in fetal death. The IUFDs with hypercoiling showed an umbilical cord stricture in 35% of cases [18 of 52]. Machin and colleagues [6] reported an incidence of 13% of fetal death associated with umbilical cord stricture in the presence of hypercoiling. We found that severity of hypercoiling was of no influence on the presence or absence of an umbilical cord stricture. As expected, we found a highly significant correlation between the length of the umbilical cord and gestational age at the time of delivery in weeks. A variety of authors found cord lengths to grow linearly. As was suggested by Leonardo da Vinci, the umbilical cord at any gestational age has usually the same length as the fetus [5]. In our study, no definite conclusion could be made about the association between UCI and cord length. The umbilical cord was not always submitted completely to pathology and therefore there is uncertainty about the total length of the umbilical cord. Maybe ‘‘short cords’’ were not short and perhaps there were ELUCs present in our study group. In cases of IUFD with hypercoiling, there were 46 cases with an umbilical cord defined as no long cord (including 16 short cords) and 30 cases with an umbilical cord defined as a long cord. There was no significant difference in the distribution of the UCI between these 2 groups. Also, there were no significant differences in length of the umbilical cord between the 4 categories of IUFD. Excessively long umbilical cords have an association with fetal death [12]. We found no ELUCs in our small group of full-term IUFDs with umbilical hypercoiling. Excessively long umbilical cords were defined as those umbilical cords measuring approximately 2 SD above the mean for full-term pregnancies. In summary, we found a negative correlation between UCI and gestational age. A higher UCI was associated with an IUFD at younger age. We hypothesized that umbilical hypercoiling leads to a reduction of umbilical cord blood flow and increased fetal cardiac workload. Consequently, umbilical hypercoiling may be associated with a disturbance of the fetal-placental circulation and this may be a possible explanation for IUFD. If hypercoiling is accepted as cause of death in the Tulip classification the ‘‘unknown’’ group decreases from 36% to 17.5% and the ‘‘umbilical cord complication’’ group increases from 2.2% to 20.6%. Therefore we recommend
UMBILICAL HYPERCOILING IN FETAL DEATH
15
that determination of the UCI should be part of the routine examination of the placentas of cases of IUFD. REFERENCES 1. Huang DY, Usher RH, Kramer MS, Yang H, Morin L, Fretts RC. Determinants of unexplained antepartum fetal deaths. Obstet Gynecol 2000;95:215–221. 2. Incerpi MH, Miller DA, Samadi R, Settlage RH, Goodwin TM. Stillbirth evaluation: what tests are needed? Am J Obstet Gynecol 1998;178:1121–1125. 3. Horn LC, Langner A, Stiehl P, Wittekind C, Faber R. Identification of the causes of intrauterine death during 310 consecutive autopsies. Eur J Obstet Gynecol Reprod Biol 2004;113:134–138. 4. Heazell AE, Martindale EA. Can post-mortem examination of the placenta help determine the cause of stillbirth? J Obstet Gynaecol 2009;29:225–228. 5. Benirschke K, Burton GJ, Baergen RN. Pathology of the Human Placenta, 6th ed. Berlin, Heidelberg: Springer-Verlag; 2012. 6. Machin GA, Ackerman J, Gilbert-Barness E. Abnormal umbilical cord coiling is associated with adverse perinatal outcomes. Pediatr Dev Pathol 2000;3:462–471. 7. 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;130:66–72. 8. Roach MR. The umbilical vessels. In: Perinatal Medicine, 13th ed. Hagerstown, MD: Harper and Row; 1976:134–142. 9. Herman A, Zabow P, Segal M, Ron-el R, Bukovsky Y, Caspi E. Extremely large number of twists of the umbilical cord causing torsion and intrauterine fetal death. Int J Gynaecol Obstet 1991;35:165–167. 10. Singh V, Khanum S, Singh M. Umbilical cord lesions in early intrauterine fetal demise. Arch Pathol Lab Med 2003;127:850–853. 11. de Laat MW, van der Meij JJ, Visser GH, Franx A, Nikkels PG. Hypercoiling of the umbilical cord and placental maturation defect: associated pathology? Pediatr Dev Pathol 2007;10:293–299. 12. Baergen RN, Malicki D, Behling C, Benirschke K. Morbidity, mortality, and placental pathology in excessively long umbilical cords: retrospective study. Pediatr Dev Pathol 2001;4:144–153. 13. Peng HQ, Levitin-Smith M, Rochelson B, Kahn E. Umbilical cord stricture and overcoiling are common causes of fetal demise. Pediatr Dev Pathol 2006;9:14–19. 14. French AE, Gregg VH, Newberry Y, Parsons T. Umbilical cord stricture: a cause of recurrent fetal death. Obstet Gynecol 2005;105: 1235–1239. 15. Kaplan AD, Jaffa AJ, Timor IE, Elad D. Hemodynamic analysis of arterial blood flow in the coiled umbilical cord. Reprod Sci 2010;17: 258–268. 16. Strong TH Jr, Jarles DL, Vega JS, Feldman DB. The umbilical coiling index. Am J Obstet Gynecol 1994;170:29–32. 17. van Dijk CC, Franx A, de Laat MW, Bruinse HW, Visser GH, Nikkels PG. The umbilical coiling index in normal pregnancy. J Matern Fetal Neonatal Med 2002;11:280–283. 18. Korteweg FJ, Gordijn SJ, Timmer A, et al. The Tulip classification of perinatal mortality: introduction and multidisciplinary inter-rater agreement. BJOG 2006;113:393–401.
16
A.C. DUTMAN AND P.G.J. NIKKELS
19. Genest DR, Singer DB. Estimating the time of death in stillborn fetuses: III. External fetal examination; a study of 86 stillborns. Obstet Gynecol 1992;80:593–600. 20. Genest DR. Estimating the time of death in stillborn fetuses: II. Histologic evaluation of the placenta; a study of 71 stillborns. Obstet Gynecol 1992;80:585–592. 21. Genest DR, Williams MA, Greene MF. Estimating the time of death in stillborn fetuses: I. Histologic evaluation of fetal organs; an autopsy study of 150 stillborns. Obstet Gynecol 1992;80: 575–584. 22. Redline RW, Ariel I, Baergen RN, et al. Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004;7:443–452. 23. Maroun LL, Graem N. Autopsy standards of body parameters and fresh organ weights in nonmacerated and macerated human fetuses. Pediatr Dev Pathol 2005;8:204–217. 24. Naeye RL. Umbilical cord length: clinical significance. J Pediatr 1985;107:278–281. 25. Frederick T. Kraus RWR, Gersell DJ, Nelson DM, Dicke JM. Placental Pathology, 1st ed. King DW, ed. Washington, DC: American Registry of Pathology, Armed Forces Institute of Pathology; 2004. 26. Predanic M, Perni SC, Chervenak FA. Antenatal umbilical coiling index and Doppler flow characteristics. Ultrasound Obstet Gynecol 2006;28:699–703. 27. Clerici G, Antonelli C, Rizzo G, Kanninen TT, Di Renzo GC. Atypical hemodynamic pattern in fetuses with hypercoiled umbilical cord and growth restriction. J Matern Fetal Neonatal Med 2013;26: 558–562. 28. Nakai Y, Imanaka M, Nishio J, Ogita S. Umbilical venous pulsation and regional circulatory disturbance. Ultrasound Med Biol 1997;23: 1165–1169. 29. Nakai Y, Imanaka M, Nishio J, Ogita S. Umbilical venous pulsation associated with hypercoiled cord in growth-retarded fetuses. Gynecol Obstet Invest 1997;43:64–67. 30. Sebire NJ. Pathophysiological significance of abnormal umbilical cord coiling index. Ultrasound Obstet Gynecol 2007;30:804–806. 31. Maalej N, Holden JE, Folts JD. Effect of shear stress on acute platelet thrombus formation in canine stenosed carotid arteries: an in vivo quantitative study. J Thromb Thrombolysis 1998;5: 231–238. 32. Vreeker A, van Stuijvenberg L, Hund TJ, Mohler PJ, Nikkels PG, van Veen TA. Assembly of the cardiac intercalated disk during preand postnatal development of the human heart. PLoS One 2014;9: e94722. 33. Angst BD, Khan LU, Severs NJ, et al. Dissociated spatial patterning of gap junctions and cell adhesion junctions during postnatal differentiation of ventricular myocardium. Circ Res 1997;80:88–94. 34. Friedman WF. The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 1972;15:87–111. 35. Bakotic BW, Boyd T, Poppiti R, Pflueger S. Recurrent umbilical cord torsion leading to fetal death in 3 subsequent pregnancies: a case report and review of the literature. Arch Pathol Lab Med 2000; 124:1352–1355.
