Prevalence of single umbilical artery, clinical outcomes and its risk factors: A cross-sectional study

Abstract Background Single umbilical artery (SUA) is found in 0.5–6% of all pregnancies worldwide. Although the association of SUA with some congenital malformations is mainly accepted, its effect on pregnancy/neonatal outcomes is still controversial. Objective This is the first study aimed to approximate the SUA prevalence in southern part of Iran. SUA epidemiologic features accompanied by some of its effects on pregnancy/neonatal outcomes are investigated as well. Materials and Methods In this cross-sectional study, data from two referral centers in Southern Iran were analyzed. In total, 1,469 pregnancies, fetuses, and neonates were examined for epidemiological features associated with SUA. SUA was confirmed by pathological examination, while congenital anomalies were diagnosed by clinical, ultrasound, and echocardiographical examinations. Data on pregnancy outcome were recorded based on the patients' medical records. Results The prevalence of SUA was 3.47% (95% CI: 2.6–4.6%). Fetal anomalies including renal, cardiac, and other congenital anomalies, intrauterine fetal death, early neonatal death, low birth weight, low placental weight, and preterm birth were significantly higher in the SUA group (OR = 68.02, 31.04, 16.03, 3.85, 11.31, 3.22, 2.70, and 2.47, respectively). However, the maternal multiparity was lower in the SUA group (OR = 0.65; 95% CI: 0.44–0.98). Conclusion A significant association was observed between SUA and increased risk of intrauterine fetal death and early neonatal death, as well as low birth weight and preterm birth. Obstetrical history of the mother like parity was identified as an important predictor of SUA. Further investigations are suggested on risk stratification of neonates in this regard.


Introduction
The umbilical cord is the carrier of fetal vein and arteries and any abnormalities in its appearance, composition, location, size, and placental and fetal attachment is associated with fetal death and congenital anomalies (1,2). Normally, the umbilical cord consists of one vein and two arteries, but the primary agenesis, secondary atresia, or persistent allantoic artery of the body stalk may result in the absence of one umbilical artery, known as single umbilical artery (SUA). Different rates of SUA have been reported for its prevalence, which may vary according to the diagnostic method used and gestational age assessed, as the highest prevalence is reported in abortus and autopsies (0.34-7%) and the lowest in live-born neonates (0.2-1.5%) (3,4). Correspondingly, the assessment of fetuses by ultrasound at 11-14 wk of gestation resulted in an incidence rate of 5.9% (5). Also, a higher prevalence (4.6-9.8%) is reported in twin pregnancies compared with singleton gestations (6).
SUA can be an isolated finding and is not considered teratogenic alone; nevertheless, previous studies reported its association with congenital anomalies or chromosomal abnormalities (4,5,7), and have the potential to increase the odds of neonatal intensive care unit (NICU) admission and mortality rate (8). It is estimated that about 30-60% of cases with SUA are concomitant with congenital abnormalities, like cardiac and genitourinary abnormalities, skeletal or gastrointestinal malformations (3,9,10), or chromosomal abnormalities, such as trisomy 13, 18, 21, and triploidy (10). Furthermore, some suggest that the associated comorbidities of SUA result in an increased risk of intrauterine fetal growth restriction (IUGR), polyhydramnios/oligohydramnios, placental abruption, placenta previa, cord prolapse, low Apgar scores, and perinatal mortality (11), while isolated SUA is not associated with increased risk of chromosomal abnormalities (12), adverse perinatal or long-term neurodevelopmental outcomes (13,14).
As each study has considered SUA in different target populations, including abortuses and autopsies, ultrasound examination, or umbilical cord pathology in fetuses born term or preterm, alive or dead, each have reported a different incidence rate, different rates of isolated SUA, associated comorbidities, or negative perinatal outcomes (9)(10)(11)(12)(13)(14)(15). Therefore, this area remains to be further explored in future studies. No previous study addressing the prevalence of SUA and its relationship with pregnancy outcomes in Iran has been published yet and thus the predictors and pathophysiology of SUA are still unknown to us.
The present study aimed to estimate the prevalence of SUA, investigate related epidemiological information, and assess its effects on pregnancy/neonate outcomes in a selected population) in a tertiary referral care center) in Southern Iran. Understanding the predictors of SUA may help us to diagnose highrisk pregnancies earlier and schedule a better prenatal care plan for them, thereby reducing the potential complications.

Study design
In this cross-sectional study, all consecutive pregnant women with gestational ages over 15 wk referred to two main referral centers (Hafez and Zeynabyie Hospitals affiliated to the Shiraz University of Medical Science, Shiraz, Iran) in southern Iran between October 2012 and October 2013 were recruited. The eligibility criterion for the study was pregnancy over 15 wk of gestational age.
A study checklist, comprising three sections, was designed for the study. In the first section, the demographic characteristics of mothers, including mothers' age, gravidity, and parity, and the gestational age at the time of delivery were recorded. In the second section, possible risk factors related to pregnancy including maternal medical conditions during pregnancy (such as gestational diabetes mellitus, chronic hypertension, preeclampsia, and epilepsy), other maternal diseases such as asthma and anemia, and use of medications was recorded. In the third section, neonatal characteristics, including gestational age at delivery, type of delivery, indications for each type of delivery, infants' sex, birth weight, the first and fifth minutes' Apgar scores, NICU admissions, and presence of significant anomalies were recorded. Renal anomalies were detected by postpartum ultrasound examination and cardiac anomalies through echocardiography.
Preterm birth was considered as childbirth at < 37 wk of gestation and low birth weight (LBW) as birth weight < 2500 gr. All data were recorded from the patients' medical records by the researcher and the missing data were taken from patients during their hospital admission.
After the delivery, the placenta and umbilical cord were sent to the pathology unit of Hazrat Zeinab Hospital in formalin containers and examined within 24 hr after delivery. All samples were examined microscopically by a pathologist who was blind to the outcome and procedure of pregnancy.

Ethical considerations
The study protocol was approved by the Ethics Committee of Shiraz University of Medical Sciences, Shiraz, Iran (Ethics code: IR.SUMS.REC.1393.4814) and all participants were informed about the study objectives and had signed a written informed consent for participation into the study.

Statistical analysis
After entering the collected data into the computer, the outliers and missing data were cleared. Data with < 7% missing data were included into the study. After descriptive results were reported, a comparison between the groups was performed using Chi-square and Student's t tests. Next, the results were reported by bivariate analysis, and multivariate analyses were defined based on the researchers' hypotheses.
Multivariate models were formed by logistic regression. The confounders were selected in each model, based on biological science. Then, backward elimination was used based on P-value

Results
Of the 1,469 pregnant women participating in this study, 51 (3.47%; 95% CI: 2.6-4.6%) had SUA and 57% of them had a female factor. Table I shows the demographic characteristics of the participants.

Effects of SUA on pregnancy outcomes
The results of 51 SUA and 1,418 double umbilical artery (DUA) pregnancies are shown in Table II. An intrauterine fetal death (IUFD), early neonatal death, preterm birth, low birth weight (LBW), low placental weight, any type of congenital anomalies, cardiac and renal anomalies were significantly higher in the SUA group compared to the DUA group (p < 0.05). However, parity was shown to be a protective factor against SUA (Table  II).

Conclusion
As indicated in the present study, a significant increase in the odds of IUFD, preterm birth, and LBW was observed in neonates with SUA. These findings could be used in counseling of women whose pregnancies are complicated by SUA. In future, appropriate antenatal surveillance could be offered to such population, which will theoretically reduce the adverse perinatal outcome of the SUA group. Evaluating the obstetrical history of the mother, such as parity, were identified as important predictors of SUA and are suggested to be studied for risk stratification of neonates.