Objective
This study compared birth parameters and the longitudinal course in physical and neurologic development between children with 2 and 3 vessel umbilical cords.
Study Design
Our study of the Collaborative Perinatal Project included singletons of at least 24 weeks’ gestation with single umbilical artery at birth and no identifiable congenital anomalies. Demographics that were collected included maternal age, race, smoking status, and socioeconomic index. Delivery data included gestational age, birthweight, Apgar scores, placental weight, and umbilical cord insertion and length. Growth and neurodevelopmental parameters were collected at various intervals from birth to 7 years.
Results
There were 263 infants with isolated single umbilical artery and 41,415 infants with 3 vessel cords. A random effect model that controlled for potential confounders did not show clinically significant differences in the physical and neurodevelopment measures between these groups.
Conclusion
Our study shows no evidence of differential longitudinal physical growth or neurologic outcomes between infants with 2 or 3 vessel cords.
The significance of single umbilical artery (SUA) has been studied for many years with varying outcomes. The association with various congenital anomalies and increased perinatal morbidity because of intrauterine growth restriction or aneuploidy has been suggested previously. The incidence of SUA ranges from 0.3–1% of all pregnancies. In >80% of cases, SUA is an isolated finding. The precise cause of SUA is not fully known. Suggested hypotheses include primary agenesis of 1 umbilical artery during development or atrophy of an umbilical artery at a later time. Pregnancy outcomes have not been attributed specifically to either of these possible causes.
For Editors’ Commentary, see Table of Contents
Many previous studies have sought to detail the perinatal and neonatal morbidity that is associated with this condition. Perinatal outcomes that have been evaluated previously in the literature include birthweight, gestational age at delivery, fetal anomalies, and neonatal intensive care unit admissions. Although the association between antenatal ultrasound findings and birth outcomes has been evaluated, there have been no data regarding long-term outcomes in affected infants. Our study aims to identify whether there are any long-term implications of SUA on physical and neurologic development. Just as the cause of SUA is unknown, the reason for associated poor outcomes in previous studies has also been unclear. Umbilical cord abnormalities may influence the placental histologic condition if there is reduced blood flow that results from mechanical or vascular causes. Increased placental abnormalities often are associated with poor neonatal outcomes. We have gathered data regarding placental features that were found with SUA in an effort to evaluate the association. The absence of a placental pathologic condition in isolated SUA cases would strengthen the proposition that this finding in isolation is not associated with adverse neonatal outcomes and, therefore, is unlikely to have long-term implications.
Materials and Methods
The Collaborative Perinatal Project (CPP) was used to obtain information regarding infants with SUA. The CPP is a well-known prospective study that enrolled pregnant women from 1959 until 1965 from 12 US medical centers. The goal of the project was to study the neurologic status of infants and birth outcomes of the pregnancy as they related to various factors. Interviews were conducted with study participants to acquire demographic information, socioeconomic status and behavioral information, and obstetric data were collected prospectively according to a predefined protocol. A socioeconomic index from the US Bureau of the Census was used, which combined education, occupation, and family income into a weighted index. Women were observed during pregnancy. At delivery, neonatal anthropometric measurements were taken, and the cord and the placenta were assessed according to specific protocols, which included the number of cord vessels. Children were observed to 7 years of age, at which time a comprehensive battery of physical and neurologic assessments was conducted. Inclusion criteria for this analysis included singleton birth of at least 24 weeks’ gestational age and a known number of umbilical arteries at birth. Study exclusion criteria included any identifiable congenital anomalies, multiple gestation, or gestational age at delivery <24 weeks.
Perinatal outcomes between pregnancies with 2- and 3-vessel cords were compared. The outcomes that were studied included gestational age at delivery, birthweight, and Apgar scores at 1 and 5 minutes. Because the embryologic cause of SUA is unknown, we were interested in the placental findings between the 2 groups. Placental morphologic and histopathologic data were gathered that included placental weight, presence of infarcts, and cord insertion.
Physical growth between the groups was also examined. Various measures of growth, which included head circumference, height, and weight, were collected at birth and again at 4 months, 8 months, 1 year, 3 years, 4 years, and 7 years.
Longitudinal data regarding neurologic development were collected and evaluated between the 2- and 3-vessel cord groups. The neurologic examination was performed by neurologists with specific training in pediatrics or pediatricians with specific training in neurology. All physicians underwent standardized training and were blinded to the child’s clinical history. Detailed information regarding the neurologic abnormalities was gathered. At 1 and 7 years, a neurologic assessment was performed that categorized children into 1 of 3 groups: normal, suspect, and abnormal. Neurologists were given detailed instructions regarding instances when an abnormal examination was elicited. If a definite abnormality was found on examination that was associated with a diagnosis, then the child was categorized as abnormal. The suspect category was used in instances in which on examination a child was not completely normal yet did not meet criteria for a definitive syndrome or neurologic diagnosis.
To facilitate interpretation, we combined suspect assessments into the normal group. Combining assessments into the abnormal category was not considered because this would raise the percentage of abnormal neurologic assessments to an unreasonably high level. Additionally, standardized psychologic testing was performed at 3 different ages. The Bayley scales of infant development were used to assess the motor, language, and cognitive abilities at 8 months of age. At the time of CPP, the Bayley scales of infant development were in a preliminary phase, and scores were not normalized as they are today but rather were specific for the CPP. Intelligence testing was performed at 4 years of age, with the Stanford Binet Intelligence scale. At age 7 years, the Weschler Intelligence Scale for Children was used. Both the Stanford Binet and Weschler scales are standardized to a mean of 100, with a standard deviation of 15.
In the unadjusted analysis, we used χ 2 tests and the Student t test for categoric and continuous variables, respectively. For all continuous measures, we applied linear regressions with generalized estimating equations and controlled for potential confounders that included maternal age, race, smoking, and the child’s sex. For neurologic assessment, we fit a logistic regression with generalized estimating equations. A global test was conducted in each regression to see whether the longitudinal trajectories are the same statistically between the study and control groups. A probability value that is < .05 is considered significant. All statistical analyses were performed with SAS software (version 9.1; SAS Institute Inc, Cary, NC).
Results
There were 59,391 pregnancies in the CPP. After excluding subjects with multiple gestations and unknown plurality (n = 3651), fetal deaths (n = 2093), gestational age <24 weeks at delivery (n = 538), infants with unknown number of umbilical arteries (n = 5441), or with anomalies detected at birth (n = 5990), 41,678 infants were included in the final data set. This number included 263 infants (0.7%) with SUA. This group was compared with 41,415 infants with 3-vessel cords.
Maternal demographic factors, newborn characteristics, and placental features were compared between the study and control populations ( Table 1 ). There was no difference between these groups with regard to education level, gravidity, or parity. Women with an SUA tended to be older, smoke during pregnancy, and have higher socioeconomic status. The proportion of female infants was higher among the single-artery group than the 2-artery group. However, there was no significant difference in gestational age at delivery or Apgar scores at 1 and 5 minutes. The number of placental infarcts and umbilical cord insertion did not vary significantly between the groups. Infants with an SUA had a slightly smaller placenta but longer umbilical cord. Tables 2 and 3 show cross-sectional comparisons between the 2 groups on child physical and neurologic development. At birth, infants with an SUA appeared smaller, but the difference disappeared thereafter. There were no consistent differences in neurodevelopment at birth, 4 months, 8 months, 1 year, 3 years, 4 years, and 7 years. To see whether the longitudinal physical and neurologic developments were different between the study and control groups, we applied generalized linear models with generalized estimating equations to the data while adjusting for confounders that included maternal demographics, sex of child, and smoking status. All joint tests of equal growth at all the age points are not statistically significant, except in body weight ( Figures 1-3 ). The specific probability values for height, head circumference, weight, intelligence testing, and neurologic measurements are .08, .25, .01, .07, and .06, respectively. Although weight shows statistically significant differences, a closer look reveals that the differences happen only at birth, 4 months, and 7 years of age and are not clinically significant (0.1 kg for birth and 4 months and 0.7 kg for 7 years).
| Arteries | |||
|---|---|---|---|
| Characteristic | 1 | 2 | P value |
| Age, y a | 25.02 ± 5.6 | 24.08 ± 6.0 | .01 |
| Race, n (%) | |||
| Non-Hispanic white | 173 (65.8) | 19106 (46.1) | .0001 |
| Non-Hispanic black | 77 (29.3) | 19134 (46.2) | |
| Others | 13 (4.9) | 3175 (7.7) | |
| Education, n (%) | |||
| Less than high school | 32 (12.6) | 7265 (17.8) | .06 |
| High school | 185 (72.5) | 28558 (70.0) | |
| Greater than high school | 38 (14.9) | 4956 (12.2) | |
| Smoking status, n (%) | |||
| Nonsmoker | 123 (47.3) | 21840 (53.1) | .01 |
| <1 cigarette/d | 3 (1.1) | 762 (1.9) | |
| 1-5 cigarettes/d | 33 (12.7) | 5374 (13.1) | |
| 6-10 cigarettes/d | 27 (10.4) | 5025 (12.2) | |
| 11-20 cigarettes/d | 54 (20.8) | 6356 (15.4) | |
| ≥21 cigarettes/d | 20 (7.7) | 1769 (4.3) | |
| Socioeconomic index, n (%) | |||
| 0-20 | 14 (5.5) | 4818 (11.9) | .01 |
| 21-40 | 85 (33.6) | 13296 (32.9) | |
| 41-60 | 73 (28.8) | 11914 (29.5) | |
| 61-80 | 52 (20.6) | 6895 (17.0) | |
| 80+ | 29 (11.5) | 3538 (8.7) | |
| Sex, n (%) | |||
| Male | 108 (41.1) | 20642 (49.8) | .004 |
| Female | 155 (58.9) | 20772 (50.2) | |
| Previous pregnancies, n (%) | |||
| 0 | 63 (24.1) | 11652 (28.3) | .33 |
| 1 | 55 (21.0) | 8878 (21.5) | |
| 2 | 41 (15.6) | 6484 (15.7) | |
| ≥3 | 103 (39.3) | 14220 (34.5) | |
| Parity, n (%) | |||
| 0 | 67 (25.5) | 12474 (30.2) | .27 |
| 1 | 58 (22.0) | 9510 (23.0) | |
| 2 | 47 (17.9) | 6795 (16.4) | |
| ≥3 | 91 (34.6) | 12551 (30.4) | |
| Gestational age at delivery, wk a | 39.3 ± 3.1 | 39.3 ± 3.2 | .71 |
| Intellegence quotient a | |||
| 4 y | 100.9 ± 15.7 | 97.6 ± 16.4 | .01 |
| 7 y | 97.2 ± 15.2 | 96.0 ± 14.7 | .26 |
| 1-Minute Apgar score, n (%) | |||
| 0-3 | 11 (4.3) | 2031 (5.1) | .81 |
| 4-6 | 35 (13.7) | 5268 (13.3) | |
| 7-10 | 203 (79.6) | 31590 (79.9) | |
| Incomplete data | 6 (2.4) | 682 (1.7) | |
| 5-Minute Apgar score, n (%) | |||
| 0-3 | 3 (1.2) | 518 (1.3) | .57 |
| 4-6 | 11 (4.4) | 1165 (2.9) | |
| 7-10 | 237 (94.4) | 37903 (95.7) | |
| Incomplete data | 0 | 30 (0.1) | |
| Placental weight, g a | 415.9 ± 92.7 | 436.8 ± 96.2 | .0008 |
| Size of infarcts, n (%) | |||
| None | 188 (76.4) | 30752 (78.4) | .26 |
| All infarcts <3 cm | 53 (21.6) | 7180 (18.3) | |
| At least 1 infarct that measures ≥3 cm | 5 (2.0) | 1281 (3.3) | |
| Cord length, cm a | 62.0 ± 15.5 | 58.7 ± 13.3 | .0005 |
| Cord around body, n (%) | |||
| None | 255 (97.7) | 40112 (97.5) | .34 |
| Tight | 2 (0.8) | 131 (0.3) | |
| Loose | 4 (1.5) | 902 (2.2) | |
| Insertion of membranes, n (%) | |||
| Marginal | 184 (75.1) | 29736 (75.7) | .99 |
| Circummarginate | 11 (4.5) | 2126 (5.4) | |
| Marginal and circummarginate | 28 (11.4) | 4237 (10.8) | |
| Circumvallate | 8 (3.3) | 1.39 (2.7) | |
| Marginal and circumvallate | 10 (4.1) | 1575 (4.0) | |
| Circummarginate and circumvallate | 3 (1.2) | 416 (1.1) | |
| Marginal, circummarginate, and circumvallate | 1 (0.4) | 127 (0.3) | |
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