Abstract
Objective:
Umbilical cord abnormalities are commonly cited as a cause of stillbirth, but details regarding these stillbirths are rare. Our objective was to characterize stillbirths associated with umbilical cord abnormalities using rigorous criteria and to examine associated risk factors.
Methods:
The Stillbirth Collaborative Research Network conducted a case-control study of stillbirth and live births from 2006-2008. We analyzed stillbirths that underwent complete fetal and placental evaluations and cause of death analysis using the INCODE classification system. Umbilical cord abnormality was defined as cord entrapment (defined as nuchal, body, shoulder cord accompanied by evidence of cord occlusion on pathologic examination); knots, torsions, or strictures with thrombi or other obstruction by pathologic examination; cord prolapse; vasa previa; and compromised fetal microcirculation which is defined as a histopathologic finding that represents objective evidence of vascular obstruction and can be used to indirectly confirm umbilical cord abnormalities when suspected as a cause for stillbirth. We compared demographic and clinical factors between women with stillbirths associated with umbilical cord abnormalities and those due to other causes as well as to live births. Secondarily, we analyzed the subset of pregnancies with a low umbilical cord index.
Results:
Of 496 stillbirths with complete cause of death analysis by INCODE, 94 (19%, 95%CI: 16-23%) were associated with umbilical cord abnormality. Forty-five (48%) had compromised fetal microcirculation, 27 (29%) had cord entrapment, 26 (27%) knots, torsions, or stricture, and five (5%) had cord prolapse. No cases of vasa previa occurred. With few exceptions, maternal characteristics were similar between umbilical cord abnormality stillbirths and non–umbilical cord abnormality stillbirths and between umbilical cord abnormality stillbirths and live births, including among a sub-analysis of those with hypo-coiled umbilical cords.
Conclusion:
Umbilical cord abnormalities are an important risk factor for stillbirth, accounting for 19% of cases, even when using rigorous criteria. Few specific maternal and clinical characteristics were associated with risk.
Precis:
Although 19% of stillbirths were attributable to umbilical cord abnormalities in a diverse U.S. cohort, few clinical characteristics were associated with useful risk factors.
Introduction:
Stillbirth, defined as fetal death occurring at or beyond 20 weeks’ gestation, occurs in 6 per 1000 pregnancies in the United States.1 Since 2003, the number of stillbirths has been stable at approximately 24,000 each year.1 Commonly referred to as a “cord accident”, stillbirth due to umbilical cord abnormality occurs when blood flow through the cord is compromised sufficiently to cause death.2,3 Umbilical cord abnormalities can be acute or chronic, as well as intermittent or persistent. Any of these can lead to inadequate delivery of oxygen and nutrients and clearance of metabolic waste. The reported rates of umbilical cord abnormalities associated with stillbirth is reported to be 2.5-30%.4-7 However, the diagnostic criteria used to define umbilical cord abnormalities in the setting of stillbirth have not been clearly defined, and confirmation of cord abnormalities as a cause of stillbirth using autopsy and placental pathology is rare.
Understanding the contribution of umbilical cord abnormalities to stillbirth is important. Stillbirths are commonly attributed to “cord accidents” without high quality data on which to base such clinical impressions. Without such data, stillbirths may be inappropriately attributed to umbilical cord abnormalities, leading to incorrect counseling, inadequate evaluation, and suboptimal care in subsequent pregnancies. Thus, our purpose was to thoroughly characterize stillbirths associated with umbilical cord abnormalities in the Stillbirth Collaborative Research Network (SCRN) study and to explore maternal and clinical factors associated with these stillbirths.
Methods:
This study is a secondary analysis of both stillbirths and live births enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development SCRN case-control study. The overall design, methods, and recruitment of the study have been previously reported.8 This study was approved by each collaboarating site institutional review board. Women were enrolled at delivery between March 2006 and September 2008. The five catchment areas were defined by state and county boundaries, including Rhode Island and portions of Massachusetts, Georgia, Texas, and Utah. Any residents of the five catchment areas who were at least 13 years of age and non-incarcerated were potentially eligible for the study. All eligible women whose delivery resulted in one or more stillborn fetuses were approached for consent, as well as a representative sample of live births, with oversampling of live births for preterm birth and non-Hispanic Black race. Stillbirth was defined by Apgar scores of 0 at 1 and 5 minutes and no signs of life by direct observation. Terminations of pregnancy with a live fetus were excluded from the study.
Gestational age was determined by the best clinical estimate using multiple sources, including information from assisted reproduction, last menstrual period, and obstetrical sonograms.8 Fetal deaths at 18 or 19 weeks without good dating were also included so that stillbirths beyond 20 weeks but with incorrect dating parameters could be enrolled. The protocol included an in-hospital interview, medical record abstraction, placental and umbilical cord gross and histopathology examination, and biospecimen collection for cases and controls. For stillbirths, a standardized postmortem examination was also performed.9-11 All participating pathologists had training in perinatal pathology, and underwent centralized workshop training to perform standardized evaluations across sites.
Our analysis included all stillbirths that underwent complete fetal autopsy and placental histopathologic evaluations, including cause of death analysis using the Initial Causes of Fetal Death (INCODE) classification system. Stillbirths with missing cause of death data were not included. The INCODE system is a hierarchical division of potential cause(s) of fetal death into probable, possible and present categories. Details have been previously published.12 A probable cause carries a high likelihood of causing the fetal death. A possible cause is one for which there is reasonable certainty that the condition is on the pathophysiologic pathway leading to death. A present cause is a condition that is documented but in remission, controlled with medications, or not deemed to be involved in the etiology of the fetal death. To determine the INCODE cause of death, the results of a standardized examination of the fetus, umbilical cord, and placenta, as well as chart abstraction and test results were obtained as a part of a recommended work-up.9-11
Umbilical cord abnormality was defined as cord entrapment (nuchal, body, or shoulder cord accompanied by evidence of cord occlusion by histopathologic exam), knots, torsions, or strictures with histopathologic evidence of thrombi or other obstruction, and evidence of fetal hypoxia, cord prolapse, vasa previa, or compromised fetal microcirculation (defined as thromboembolism of the umbilical vein, large fetal vessels, or thromboembolism of villous fetal capillaries and avascular villi with evidence of obstruction).12,13 This expands the original INCODE criteria for umbilical cord abnormalities, which included only cord entrapment, knots, torsions, or strictures, cord prolapse, and vasa previa. The definition was expanded for this analysis due to subsequent recognition of umbilical vein thrombosis as an important finding in umbilical cord abnormality-associated stillbirth.14 Only cases wherein umbilical cord abnormality was considered a probable or possible cause of death based on INCODE were considered umbilical cord abnormality stillbirths.
Demographic and clinical variables, including sociodemographic, medical, psychosocial, and reproductive history variables, were selected for analysis based on their potential associations with stillbirth. These variables were compared between women with stillbirths attributable to umbilical cord abnormality (umbilical cord abnormality stillbirths) and women with stillbirths due to other causes (non–umbilical cord abnormality stillbirths), as well as with women with live births with adequate placental examination. A sub-analysis was performed according to umbilical cord index (, in coils per cm of cord length), which was categorized as high (umbilical cord index > 0.3 coils/cm), intermediate (0.07-0.3 coils/cm), or low (umbilical cord index < 0.07coils/cm), since umbilical cord index has been associated with stillbirth.15
This analysis was performed using SAS software, Version 9.4 of the SAS System for Windows (SAS, Inc., Cary, NC), and the unit of analysis was the pregnancy. Categorical variables were compared using Fisher’s exact and chi-square analyses and continuous variables were assessed using t-test. No corrections for multiple comparisons were made. P-values were considered significant if less than 0.05. Data were weighted for this analysis to account for study design of over- and under-sampling of racial or ethnic groups and gestational age at delivery. Use of analytical weights yields live birth estimates that more closely approximate the general population of live births in the five geographic catchment areas during SCRN enrollment. The methods for calculation of weighted data have been previously described.8
Results:
A total of 496 pregnancies complicated by stillbirth and 1,447 women with pregnancy ending in live birth met study inclusion criteria for the primary analysis (Figure 1). Of stillbirths, 94 (19%, 95%CI 16-23%) were attributed to umbilical cord abnormalities. Of these, 45 (48%) had compromised fetal microcirculation, 27 (29%) had cord entrapment, 26 (27%) had knots, torsions, or stricture, and 5 (5%) had a cord prolapse. No cases of vasa previa were identified (Table 1). Just over half of umbilical cord abnormality stillbirths occurred after 32 weeks (Figure 2).
Figure 1.
Eligibility flow diagram. *Items not mutually exclusive.
Table 1:
Umbilical cord abnormality sub-types among stillbirths according to likelihood of umbilical cord abnormality as a cause of death by INCODE
| Umbilical cord abnormality sub-type | Overall N=94a |
Subset | |
|---|---|---|---|
| Probable N=60 |
Possible N=34 |
||
| Compromised fetal microcirculation | 45 (48.) | 22 (36) | 24 (69) |
| Cord entrapment | 27 (29) | 17 (30) | 10 (31) |
| Knots/torsions/strictures | 26 (27) | 26 (43) | 0 |
| Cord prolapse | 5 (5) | 5 (8) | 0 |
| Vasa previa | 0 | 0 | 0 |
Due to overlap between compromised fetal microcirculation and other causes, percentages do not add up to 100.
Figure 2.
Timing of stillbirth by cause of death. Overall P=.004 for umbilical abnormality versus nonumbilical cord abnormality stillbirth distributions across gestational periods.
There were no differences in demographic or socioeconomic factors in women with umbilical cord abnormality stillbirths compared to women with non–umbilical cord abnormality stillbirths (Table 2). Compared with women with live births, women with umbilical cord abnormality stillbirths were more often obese (Table 2).
Table 2.
Demographic characteristics
| Characteristic | Stillbirths | P-value UCA vs non-UCA |
Live birth n=1285 |
P-value UCA stillbirths vs Live birth |
|
|---|---|---|---|---|---|
| UCA n=94 |
Non-UCA n=395 |
||||
| Maternal age (years) at delivery, mean (SD) | 27.0 (7.4) | 27.6 (6.6) | 0.519 | 27.5 (5.7) | 0.591 |
| Maternal race/ethnicity | |||||
| white non-Hispanic | 32 (34) | 136 (34) | 0.093 | 603 (47) | 0.098 |
| black, non-Hispanic | 14 (15) | 103 (26) | 144 (11) | ||
| Hispanic | 41 (44) | 130 (33) | 438 (34) | ||
| Other | 7 (7) | 26 (7) | 101 (8) | ||
| Born in the USA | |||||
| Yes | 71 (81) | 290 (77) | 0.434 | 983 (80) | 0.899 |
| No | 17 (19) | 87 (23) | 242 (20) | ||
| Insurance/method of payment | |||||
| no insurance | 6 (7) | 24 (6) | 0.925 | 45 (3) | 0.327 |
| any public/private | 47 (50) | 205 (52) | 600 (47) | ||
| Veterans Affairs/ co | 41 (43.) | 164 (42) | 638 (50) | ||
| Maternal education, years, mean (SD) | 13.3 (2.8) | 13.0 (2.9) | 0.300 | 13.5 (2.9) | 0.534 |
| Maternal education, grade categorized | |||||
| 0-11 (none/primary) | 17 (19) | 82 (22) | 0.746 | 219 (18) | 0.812 |
| 12 (completed second | 23 (27) | 109 (29.) | 299 (24) | ||
| 13+ (college) | 47 (54) | 185 (49) | 702 (58) | ||
| Family income last 12 months | |||||
| only public/private | 9 (10) | 31 (8.4) | 0.852 | 69 (6) | 0.426 |
| assistance and personal income | 29 (33) | 133 (36) | 442 (36) | ||
| only personal income | 48 (56) | 209 (56) | 704 (58) | ||
| Marital status/cohabitating | |||||
| not married or cohabitating | 18 (21) | 102 (27) | 0.240 | 180 (15) | 0.181 |
| cohabitating / married | 69 (79) | 275 (73) | 1045 (85) | ||
| Parity | |||||
| Nulliparous | 44 (47) | 176 (45) | 0.730 | 461 (36) | 0.062 |
| Multiparous | 50 (53) | 219 (55) | 816 (64) | ||
| Maternal BMI, mean (SD) | 28.4 (7.3) | 27.3 (6.8) | 0.179 | 26.3 (6.4) | 0.009 |
| Maternal BMI categorized | |||||
| BMI < 30 | 59 (65) | 278 (72) | 0.208 | 964 (77) | 0.026 |
| 30+ (obese) | 32 (35) | 107 (28) | 285 (23) | ||
UCA, umbilical cord abnormalities; SE, standard error; BMI, body mass index
Column totals reflect weighted adjustment for over- and under-representation of population groups. Unweighted column totals: 90 UCA, 406 non-UCA, 1447 livebirth.
P-values reported from Wald chi-square for categorical variables, or two-sample t-test for continuous variables.
Medical and obstetric characteristics of umbilical cord abnormality and non–umbilical cord abnormality stillbirths are depicted in Table 3. Compared to non–umbilical cord abnormality stillbirths, umbilical cord abnormality stillbirths occurred an average of 3.2 weeks later in pregnancy. Otherwise, no differences were identified between umbilical cord abnormality and non–umbilical cord abnormality stillbirth cases . Compared to women with live births, women with umbilical cord abnormality stillbirths were less likely to have TSH ≥ 2.5 uIU/mL. While a clinical history of hypertension, diabetes, and multifetal pregnancy were marginally associated with umbilical cord abnormality stillbirth, no other significant differences were identified, including alcohol or drug exposure, and hypertensive disorders of pregnancy (Table 3).
Table 3.
Clinical characteristics
| Characteristic | Stillbirths | P-value UCA vs non-UCA |
Live births n=1285 |
P-value UCA stillbirths vs live births |
|
|---|---|---|---|---|---|
| UCA n=94 |
Non-UCA n=395 |
||||
| No Prenatal Care | 4 (4) | 39 (10) | 0.023 | 37 (3) | 0.690 |
| Chronic Hypertension | 11 (11) | 39 (10) | 0.695 | 69 (5) | 0.096 |
| Asthma | 9 (10) | 37 (10) | 0.976 | 93 (8) | 0.525 |
| Seizures | 2 (2) | 11 (3) | 0.779 | 21 (2) | 0.709 |
| Pre-gestational Diabetes | 5 (6) | 22 (5) | 0.972 | 15 (1) | 0.113 |
| Thyroid Disorder | 3 (3) | 15 (4) | 0.796 | 54 (4) | 0.562 |
| Kidney Disease | 1 (2) | 6 (2) | 0.953 | 7 (1) | 0.528 |
| Sickle cell disease | 0 | 0 | - | 0 | - |
| Autoimmune Disorder | 1 (1) | 0 | - | 13 (1) | 0.796 |
| Mental illness | 8 (9) | 27 (7) | 0.569 | 85 (7) | 0.484 |
| UTI during pregnancy | 11 (12) | 56 (15) | 0.506 | 188 (15) | 0.382 |
| TSH (uIU/mL) | |||||
| TSH ≥ 2.5 | 19 (23) | 93 (26) | 0.543 | 437 (41) | <0.001 |
| TSH < 0.1 | 1 (1) | 5 (1) | 0.741 | 3 (0) | 0.480 |
| Assisted reproductive technology | 3 (3) | 18 (4) | 0.466 | 50 (4) | 0.623 |
| Umbilical cord cotinine (ng/mL) | 11 (13) | 64 (18) | 0.257 | 94 (9) | 0.293 |
| Alcohol use during pregnancy | 1 (1) | 12 (3) | 0.150 | 19 (2) | 0.661 |
| Tobacco use during pregnancy | 11 (12) | 49 (13) | 0.776 | 90 (7) | 0.219 |
| Drug use during pregnancy | 2 (2) | 12 (3) | 0.694 | 31 (2) | 0.945 |
| Abuse (physical, sexual, or emotional) | 2 (3) | 5 (1) | 0.517 | 28 (2) | 0.826 |
| Multifetal pregnancy | 6 (6) | 27 (7) | 0.785 | 15 (1) | 0.053 |
| Presenting symptom - Vaginal bleeding | 2 (3) | 33 (9) | 0.024 | 10 (1) | 0.332 |
| Preeclampsia | 8 (9) | 44 (12) | 0.435 | 91 (7) | 0.658 |
| GA of stillbirth (weeks), mean (SD) | 30.6 (7.6) | 27.4 (6.9) | <.001 | ||
| male | 41 (47) | 198 (54) | 0.222 | 631 (50) | 0.624 |
| female | 47 (53) | 166 (46) | 639 (50) | ||
| LBW <2500g | 31 (37) | 68 (19) | 0.003 | 1213 (98) | <.001 |
| Stillbirth timing | |||||
| Intrapartum | 9 (9) | 79 (20) | 0.006 | ||
| Antepartum | 85 (91) | 316 (80) | |||
UCA, umbilical cord abnormalities; SE, standard error; UTI, urinary tract infection; TSH, thyroid stimulating hormone.
Column totals reflect weighted adjustment for over- and under-representation of population groups. Unweighted column totals: 90 UCA, 406 non-UCA, 1447 livebirth.
P-values reported from Wald chi-square for categorical variables, or two-sample t-test for continuous variables. P-values are not reported where cell counts are zero.
Among the subset of 1331 women included in analysis of umbilical cord index, there were a total of 357 deliveries with a high umbilical cord index, 709 with intermediate, and 168 with low umbilical cord index. Neither high umbilical cord index (present in 30% of stillbirths and 28% of live births, p=0.609) nor intermediate umbilical cord index (present in 53% of stillbirths and 59% of live births, p=0.061) were associated with stillbirth overall. Low umbilical cord index was significantly associated with stillbirth overall (17% of stillbirths versus 12% of live births; OR: 1.4, 1.02-2.01). To assess the robustness of the association between Low umbilical cord index and stillbirth, we estimated an adjusted logistic regression model of stillbirth weighted for sampling design. Covariates considered for inclusion were factors with differences between groups in Table 3, with the final model including low umbilical cord index, parity and hypertension. After adjusting for parity and hypertension, low umbilical cord index remained significantly associated with SB (aOR: 1.5, 1.1-2.1). In the sub-cohort of pregnancies with low umbilical cord index, women with umbilical cord abnormality stillbirths were more educated, had higher BMI, and delivered later compared to non–umbilical cord abnormality stillbirths. Stillbirths differed from live births in that women with pregnancies ending in stillbirth had higher average BMI (Table 4). Among pregnancies with low umbilical cord index, the only factors that distinguished umbilical cord abnormality stillbirths from both live births and non–umbilical cord abnormality stillbirths was BMI.
Table 4.
Clinical characteristics among pregnancies with Low Umbilical Cord Index (UCI) (≤ 0.07)
| Characteristic | Stillbirths | P-value-value UCA vs non-UCA |
Live births n=104 |
P-value UCA stillbirths vs live births |
|
|---|---|---|---|---|---|
| UCA n=14 |
Non-UCA n=50 |
||||
| Maternal age (years) at delivery, mean (SD) | 30.6 (8.0) | 26.4 (6.0) | 0.083 | 27.1 (5.4) | 0.126 |
| Maternal education, years, mean (SD) | 14.9 (3.6) | 12.3 (3.2) | 0.037 | 13.6 (3.1) | 0.265 |
| Nulliparous | 3 (25) | 22 (43) | 0.188 | 35 (33) | 0.516 |
| Maternal BMI, mean (SD) | 31.0 (7.0) | 26.1 (5.3) | 0.022 | 26.1 (5.3) | 0.014 |
| Maternal BMI ≥ 30 | 7 (48) | 9 (19) | 0.066 | 25 (24) | 0.111 |
| Chronic Hypertension | 2 (15) | 4 (8) | 0.511 | 2 (2) | 0.201 |
| Asthma | 0 | 6 (13) | - | 5 (5) | - |
| Seizures | 0 | 1 (2) | - | 2 (2) | - |
| Pre-gestational Diabetes | 0 | 3 (7) | - | 1 (1) | - |
| Thyroid Disorder | 2 (12) | 1 (2) | 0.215 | 1 (1) | 0.196 |
| Kidney Disease | 0 | 1 (2) | - | 0 | - |
| Sickle cell disease | 0 | 1 (3) | - | 0 | - |
| Autoimmune Disorder | 1 (5) | 0 | - | 0 (0) | 0.354 |
| Mental illness | 3 (26) | 5 (11) | 0.308 | 7 (7) | 0.195 |
| UTI during pregnancy | 1 (10) | 7 (16) | 0.589 | 13 (13) | 0.797 |
| TSH (uIU/mL) | |||||
| TSH ≥ 2.5 | 5 (38) | 11 (34) | 0.371 | 34 (40) | 0.928 |
| TSH < 0.1 | 0 | 0 | - | 0 | - |
| Assisted reproductive technology | 1 (5) | 0 | - | 8 (8) | 0.677 |
| Alcohol use during pregnancy | 0 | 1 (2) | - | 1 (1) | - |
| Tobacco use during pregnancy | 1 (8) | 5 (10) | 0.907 | 6 (6) | 0.722 |
| Drug use during pregnancy | 0 | 2 (3) | - | 2 (2) | - |
| Abuse (physical, sexual, or emotional) | 0 | 0 | - | 1 (1) | - |
| Presenting symptom - Vaginal bleeding | 0 | 6 (12) | - | 1 (1) | - |
| Preeclampsia | 2 (18) | 8 (17) | 0.984 | 10 (10) | 0.544 |
| GA of stillbirth (weeks), mean (SD) | 32.5 (7.6) | 27.6 (7.1) | 0.029 | - | - |
| male | 7 (51) | 25 (51) | 0.997 | 50 (48) | 0.817 |
| female | 7 (49) | 24 (49) | 54 (52) | ||
| LBW <2500g | 7 (50) | 9 (19) | 0.052 | 102 (98) | 0.004 |
| Stillbirth timing | |||||
| Intrapartum | 1 (5) | 13 (26) | 0.030 | - | |
| Antepartum | 13 (95) | 37 (74) | |||
UCA, umbilical cord abnormalities; SE, standard error; BMI, body mass index; UTI, urinary tract infection; TSH, thyroid stimulating hormone.
Column totals reflect weighted adjustment for over- and under-representation of population groups. Unweighted column totals: 13 UCA, 106 non-UCA, 233 livebirth. All comparisons include sampling weights. P-values reported from Wald chi-square, for categorical variables, or two-sample t-test for continuous variables. P-value not reported in presence of zero cells.
We also evaluated umbilical cord index on a continuum, there was significant differences across all deciles in stillbirth, however, not in a manner indicative of a pattern of increasing or decreasing trend. The highest percentages of stillbirth occurring in the 1st, 4th, 5th and 10th decile. Of note, when comparing a umbilical cord index of zero to any higher umbilical cord index, umbilical cord index of zero were twice more frequently seen among stillbirths vs livebirths (10% vs 5%, p = 0.002).
The above results did not change when we compared women with missing umbilical cord index data to women with umbilical cord index available (Appendixes 1 and 2) .
Discussion:
In a prospective study with high-quality data and rigorous cause of death analysis, we found that 19% of all stillbirths and 28% of stillbirths at or beyond 32 weeks were associated with umbilical cord abnormalities.
Umbilical cord abnormality included five conditions or pathways: cord entrapment, knots, torsions, or strictures, cord prolapse, vasa previa, and compromised fetal microcirculation. Cord entrapment, which includes nuchal, body, or shoulder cord, is a common finding at birth and while even multiple nuchal loops are not associated with stillbirth, cord entrapment is associated with adverse intrapartum events.16-19 Umbilical cord knots, torsions or strictures are reported to occur in 0.3-2.1% of pregnancies with a stillbirth rate of 8-11%.20-23 In the absence of histopathologic confirmation of umbilical cord abnormality as a cause of death, these studies are difficult to interpret, especially since nuchal cords and true knots are common findings that result in healthy live births in a majority of cases.16-19,24 Cord prolapse usually occurs following preterm prelabor rupture of membranes and is associated with a high rate of perinatal mortality.25 While mortality is high if cord prolapse occurs, it accounted for only 9% of umbilical cord abnormality stillbirths and 1% of stillbirths overall in our study. Vasa previa occurs when the fetal vessels traverse the membranes overlying the internal cervical os. This occurs rarely and when diagnosed prenatally, has a low perinatal mortality.26-28 Finally, compromised fetal microcirculation is a histopathologic finding that represents objective evidence of vascular obstruction and can be used to indirectly confirm umbilical cord abnormality when it is suspected as a cause for stillbirth. In this cohort, compromised fetal microcirculation was coded as a “possible” cause of death when it was present without clinical evidence of cord obstruction and as a “probable” cause when both the histopathologic criteria were met and clinical evidence of obstruction was present. With that being said, there is always the possibility of an overlap in conditions and pathways leading to fetal stillbirth.
Abnormal umbilical cord index is associated with adverse perinatal outcomes such as fetal heart rate decelerations, operative vaginal delivery, preterm birth, and stillbirth.29-31 In our cohort, high umbilical cord index was not associated with stillbirth while low umbilical cord index was. This adds to a body of literature reporting mixed results regarding high umbilical cord index15,29-32 but consistent associations of low umbilical cord index with adverse events.15,29,31,33 Several studies tested the association between prenatally-assessed umbilical cord index and adverse outcomes with mixed results.32,33 Mittal, Nanda and Sen prospectively assessed 200 pregnancies for umbilical cord index using ultrasound between 20-24 weeks’ gestation and found a low umbilical cord index to be associated with preterm contractions, oligohydramnios, intrapartum fetal heart rate abnormalities, operative vaginal delivery, and low birth weight.33 Ma’ayeh et al prospectively assessed 72 women for high umbilical cord index using ultrasound in the 2nd trimester but did not identify associations with adverse outcomes.32 Taken together, the clinical significance of umbilical cord index, whether identified prenatally or after an adverse event such as stillbirth, remains uncertain.
Previous studies were comprised primarily of retrospectively reviewed case series and case-control studies, such that the reported contribution of umbilical cord abnormalities to stillbirth varies widely, from 8% to 65%.34-38 Given the high frequency of nuchal cords and true knots in uncomplicated live births, there has been understandable skepticism when stillbirths are attributed to the umbilical cord abnormality. A previous analysis of SCRN data reported that approximately 10% of stillbirths were associated with umbilical cord abnormality.13 The rate of umbilical cord abnormality-associated stillbirth is higher in this analysis because of our inclusion of umbilical vein thrombosis in the definition of umbilical cord abnormality based on data supporting its role in umbilical cord abnormality-associated stillbirth.14 Our data establish an important baseline rate of umbilical cord abnormality stillbirths and confirm cord abnormalities as a substantial contributor to stillbirths in the United States population.
While we identified minor differences between umbilical cord abnormality stillbirths and live births, these factors were not different between umbilical cord abnormality stillbirths and non–umbilical cord abnormality stillbirths, such that they do not lend themselves to practical use for risk stratification. Among pregnancies with low umbilical cord index, maternal BMI was higher and among umbilical cord abnormality stillbirths than both non–umbilical cord abnormality stillbirths and live births. Of note, although this was statistically important finding, the actual BMI distribution are not different, which means that the finding was not clinically helpful. The relevance of these differences is unclear as there is not an apparent biologically plausible explanation.
A previous analysis of the SCRN cohort found that a higher proportion of stillbirth was associated with umbilical cord abnormality in non-Hispanic white women compared to other groups.13 However, race and ethnicity were not associated with umbilical cord abnormality stillbirth in this analysis. Differences between the two analyses include the definition of umbilical cord abnormality and the incorporation of sampling weights to account for over-sampling and ensure population-level representation for comparisons between stillbirths and live births. Because the rate of umbilical cord abnormality stillbirths is relatively low in all racial or ethnic groups, race and ethnicity are unlikely to be a useful predictor of umbilical cord abnormality stillbirth, whether or not the proportion of umbilical cord abnormality-attributable stillbirths truly varies across race and ethnicity.
Our study has multiple strengths. The prospective data collection, standardized evaluation protocols and unbiased recruitment strategy maximize data quality. The centralized training of perinatal pathologists, development and use of the INCODE system and confirmation of umbilical cord abnormality with placental and fetal histopathology also contributed to high data quality. In addition, we had a relatively large number of well-characterized stillbirths in a racially, ethnically and geographically diverse population. A limitation of our study was the lack of pathologist blinding to clinical circumstances. Also, our ability to sub-analyze umbilical cord abnormality stillbirths by type was limited by sample size, despite having a large cohort of umbilical cord abnormality associated stillbirths . A final consideration is that because there is no gold standard for cause of death for stillbirth, INCODE is a useful assessment tool but not a definitive determination. Accordingly, we can report on stillbirths associated with umbilical cord abnormality but we cannot be certain that umbilical cord abnormality was the definitive “cause of death.”
Our data underscore the need for further investigation into the prediction and prevention of stillbirths due to umbilical cord abnormality. This is especially important since most of these stillbirths occur relatively late in pregnancy in the setting of otherwise normal fetuses and pregnancies. Given a lack of clear risk factors, strategies should target the entire population. Studies are needed to characterize and evaluate systematic ultrasonographic evaluation of the umbilical cord. Based on our current state of knowledge of this condition, prevention efforts would potentially lead to excessive intervention that might cause more harm than good. For example, identification of nuchal cord alone is insufficient given its high incidence (up to 25%) and low specificity for stillbirth.16 However, other sonographic measurements may better predict umbilical cord abnormality and risk for stillbirth. Investigations into biomarkers indicating intermittent hypoxia may also be of value in identifying pregnancies with occult but clinically relevant umbilical cord abnormalities or occlusion.
Supplementary Material
Acknowledgements:
This work, including the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review and approval of the manuscript, was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development: U10-HD045953 Brown University, Rhode Island; U10-HD045925 Emory University, Georgia; U10-HD045952 University of Texas Medical Branch at Galveston, Texas; U10-HDO45955 University of Texas Health Sciences Center at San Antonio, Texas; U10-HD045944 and 1K12 HD085816 University of Utah Health Sciences Center, Utah; and U01-HD045954 RTI International, RTP. The study received funding support from the R Baby Foundation.
Footnotes
Financial Disclosure
Deborah Conway disclosed receiving funds from the University of South Florida Morsani School of Medicine. The other authors did not report any potential conflicts of interest.
Each author has confirmed compliance with the journal’s requirements for authorship.
Presented at the 2016 Society for Maternal Fetal Medicine Annual Meeting in Las Vegas, NV, May 14–17, 2016.
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