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单纯性单脐动脉:评估不良妊娠结局的风险

European Journal of Obstetrics & Gynecology and Reproductive Biology, pages 80 - 83

Abstract

Objective

To evaluate if isolated single umbilical artery (SUA) diagnosed on second-trimester ultrasound has an independent risk association with adverse pregnancy outcomes.

Study design

We compared 136 singleton pregnancies with isolated SUA with 500 consecutive singleton pregnancies with a three-vessel cord (3VC). Pregnancies complicated by chromosomal abnormalities and other congenital malformations were excluded. The rates of intrauterine growth restriction (IUGR) defined as birth weight less than the 3rd percentile, small for gestational age (SGA) fetuses, defined as a birth weight lower than the 10th percentile and the incidence of very preterm deliveries before 34 weeks of gestation were compared between the two groups. Multivariable logistic regression analysis was performed to evaluate the risk association between SUA and adverse pregnancy outcomes, while controlling for potential confounders.

Results

Fetuses with isolated SUA had significantly lower birth weight (2942.5 ± 783.7 vs. 3243.7 ± 585.6 g,p = 0.002), and were delivered at an earlier gestational age (38.7 ± 3.4 vs. 39.5 ± 2.2 weeks,p < 0.001), when compared to fetuses with a 3VC. Fetuses with isolated SUA were at higher risk for IUGR (15.4% vs. 1.8%,p < 0.001), SGA (20.6% vs. 4.4%,p < 0.001) and very preterm delivery (6.6% vs. 1.4%,p = 0.002). Using a multiple logistic regression model, isolated SUA was shown to be an independent risk factor for IUGR (adjusted OR = 11.3, 95% CI 4.8–25.6;p < 0.001) and very preterm delivery (adjusted OR = 5.0, 95% CI 1.8–13.8;p = 0.002).

Conclusions

The presence of isolated SUA is independently associated with an increased risk for IUGR, SGA and very preterm delivery.

Keywords: Single umbilical artery, Perinatal outcome, IUGR, SGA, Preterm delivery.

Introduction

The absence of one umbilical artery, which represents the most common anatomical abnormality of the umbilical cord, is found in 0.2–2.0%[1], [2], [3], and [4]of deliveries. The pathogenesis of this condition, known as single umbilical artery (SUA), is uncertain. Aplasia or atrophy of the missing vessel has been suggested in the etiology [5] . Fetuses with SUA are considered at increased risk of chromosomal and structural abnormalities and increased adverse perinatal outcome, such as perinatal mortality, growth restriction and preterm labor[2], [3], [6], and [7]. Despite these associations, controversy exists regarding the clinical significance of SUA as an isolated finding in a low-risk patient population. Some of the current literature did not demonstrate an increased risk of IUGR in anatomically normal fetuses with SUA and the authors suggested that the remaining artery in SUA fetuses carries twice the blood volume of an artery in a 3VC[4], [8], and [9]. Other studies reported that the finding of SUA is associated with increased incidence of fetal growth restriction, prematurity and perinatal mortality and recommended serial sonograms for fetal growth and close obstetric follow-up[3], [10], [11], [12], and [13].

While other authors have placed much emphasis on the association between SUA and aneuploidy or co-existing anomalies[1], [2], [5], [6], [7], [10], [11], and [12], the aim of our study was to estimate the rates of adverse pregnancy outcome in a low-risk patient population. Therefore, we included only fetuses without known chromosomal abnormalities and associated major congenital anomalies and evaluated the risk of intrauterine growth restriction (IUGR), small for gestational age (SGA) fetuses and the incidence of deliveries before 34 gestational weeks compared to a control group of 500 fetuses with a three-vessel cord (3VC) using a robust, prospectively obtained database.

Materials and methods

This is a retrospective cohort study of consecutive patients, with a two-vessel umbilical cord, who received second-trimester ultrasonography at our tertiary referral center between 2004 and 2011 as part of routine antenatal care. Study approval was obtained from the institutional review board of the Medical University of Vienna (ECS 1160-2013). Demographic information, maternal medical and obstetrical history, ultrasonographic findings, and genetic screening or diagnostic results are entered into a prospective perinatal database at the time of the ultrasound examination for all patients seen at our institution. Additionally, all pregnancy and neonatal outcome information, assessed by a neonatologist, was entered into this database. A SUA was diagnosed by visualizing two vessels on a cross section of the umbilical cord. If necessary, color flow mapping was used to visualize the umbilical arteries adjacent to the fetal bladder. When SUA was suspected, a detailed second trimester fetal anomaly scan was undertaken according to routine clinical practice and the patients were offered fetal karyotyping. Doppler flow indices of the uterine and the umbilical artery were performed in all cases at 20–25 weeks of gestation. We measured the Pulsatility Index (PI) of the umbilical artery in each fetus together with PI flow measurements and notch evaluation of the uterine arteries was obtained. All measurements were performed in accordance to the guidelines of the International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) ( www.isuog.org ).

Primary outcomes included the risk of IUGR, small for gestational age fetuses (SGA), intrauterine fetal death (IUFD) and very preterm delivery in cases of isolated SUA.

Estimation of fetal weight was calculated by applying the Hadlock formula using composite measures of fetal biometry [14] . IUGR was defined as birth weight less than the 3rd percentile and SGA was defined as a birth weight less than the 10th percentile. Very preterm delivery was defined as a delivery before 34 gestational weeks and IUFD was defined as fetal death at 20 weeks or more of gestation.

The institution's perinatal database was the used to identify 500 consecutive pregnancies with a 3VC, which were seen during the same time period at our institution's outpatient clinic. All baseline characteristics as well as the incidence of the primary outcomes were compared between patients with and without isolated SUA. Additionally we controlled for potential confounders such as obesity, defined as a BMI >30, tobacco use, gestational diabetes with insulin treatment, hypertension and methadone abuse. Given the known risk of adverse pregnancy outcome in fetuses with aneuploidy and severe malformations, all cases with chromosomal abnormalities and major fetal anomalies were excluded.

Statistical analysis

In this cohort study we used descriptive statistics for analyses of patients’ demographic data. Values are given as mean (standard deviation [SD]) when normally distributed or as median (range) at presence of skewed distribution. Student'st-test was used to compare continuous variables, and Chi square test and Fisher's exact test was used to compare categorial variables. For multivariable analysis a logistic regression model was used entering preterm birth or presence of IUGR as dependent variable and risk factors as covariates. The statistical software SPSS 18.0 for Windows (SPSS 18.0, SPSS Inc, Chicago, IL, USA) was used for statistical analyses.p-Values of <0.05 were considered statistically significant.

Results

In total, 209 cases of SUA were identified during the 8-year study period, giving an incidence of 1.4% in our patient population. Seven (3.3%) fetuses showed chromosomal abnormalities (Trisomy 21 (n = 1), Trisomy 18 (n = 4), Trisomy 9 (n = 1) and chromosomal mosaicism (n = 1)). All fetuses with karyotype aberrations showed other malformations affecting the central nervous system (n = 2), the heart (n = 4) or the urogenital system (n = 1). Twenty (9.6%) chromosomally normal fetuses presented with other major structural anomalies: Ten fetuses showed congenital heart defects (atrioventricular valve dysplasia (n = 2), Tetralogy of Fallot (n = 3), double outlet right ventricle (n = 2), ventricular septal defect (n = 3)). In 10 cases structural malformations affected the following systems: musculoskeletal (n = 2), gastrointestinal (n = 1), urogenital (n = 4) and central nervous system (n = 3). Additionally, 18 (8.3%) twin pregnancies were observed (dichorionic (n = 16); monochornionic (n = 2)). Cases with congenital malformations, chromosomal anomalies and multiple pregnancies were excluded from the cohort. Additionally 28 (13.4%) patients had to be excluded because they were referred from other hospitals for a second opinion sonogram and data on pregnancy outcome was missing. In total, 136 fetuses showed single umbilical artery as an isolated finding and delivered at our center. These cases were used for analysis. Maternal demographics and pregnancy characteristics for our population are shown in Table 1 . Twenty-five (18.4%) women opted for prenatal karyotyping revealing normal test results. The remaining pregnancies resulted in healthy infants, therefore no additional karyotypes were obtained in the postnatal period. Patients with fetuses with isolated SUA were found to have a comparable BMI at the time of ultrasound examination and similar rates of hypertension, preeclampsia, gestational diabetes, tobacco use and substance abuse compared to patients with a 3VC (n = 500).

Table 1 Patients’ characteristics (n = 636).

  N or mean % or SD
Maternal age (years) 28.6 6.5
Gravidity 2.7 1.6
Parity 1.1 1.1
Gestational age at ultrasound (weeks) 21.4 4.7
BMI > 30 84 13.2%
Diabetes 51 8%
Preeclampsia 9 1.4%
Cigarette smoking 173 27.2%
Substance use 13 2%
Fetal sex (female) 306 48.1%

BMI, body mass index, SD, standard deviation.

Patients with isolated SUA delivered earlier than patients without SUA (38.7 ± 3.4 weeks vs. 39.5 ± 2.2 weeks, mean difference: 0.8 weeks,p = 0.002) and birth weights were significantly lower in neonates with SUA (2942.5 ± 783.7 g vs. 3243.7 ± 585.6 g, mean difference 301.2 g,p < 0.001) compared to the 3VC group. Results of the univariate analyses are provided in Table 2 . The rate of very preterm delivery before 34 weeks of gestation was increased in pregnancies with SUA (p = 0.002) even after controlling for BMI >30, hypertension, preeclampsia, gestational diabetes, cigarette smoking and methadone abuse ( Table 3 ). Patients with isolated SUA were at increased risk for IUGR compared to those without SUA (15.4% versus 1.8%;p < 0.001) ( Table 2 ). The association between SUA and IUGR (adjusted OR 5.0, 95% CI 1.8–13.8,p = 0.002) remained statistically significant even after controlling for potential confounders ( Table 3 ). Patients with isolated SUA were also at increased risk for SGA compared to those without (20.6% versus 4.4%;p < 0.001) ( Table 2 ). In 4 (1.8%) cases of IUGR fetuses and in 5 (2.3%) cases of appropriate for gestational age fetuses notching in the uterine arteries was observed. No patient developed preeclampsia. Doppler velocimetry measurements of the umbilical artery showed pathological results in 3 (1.4%) cases. Of these, 2 fetuses had an IUGR.

Table 2 Characteristics of women diagnosed with isolated single umbilical artery compared with controls.

  Single umbilical artery (n = 136) Controls (n = 500) Odds ratio p-Value
  N or mean % or SD N or mean % or SD    
Gestational age at delivery (weeks) 38.7 3.4 39.5 2.2 N/A 0.002 b
Preterm birth before 34 weeks 9 6.6% 7 1.4% 5.0 0.002 a
Birth weight (g) 2942.5 783.7 3243.7 585.6 N/A <0.001 b
IUGR 21 15.4% 9 1.8% 10.0 <0.001 a
Birth weight <10th percentile 28 20.6% 22 4.4% 5.6 <0.001 a
BMI > 30 17 12.5% 67 13.4% 0.9 0.89 a
Diabetes 12 8.8% 39 7.8% 1.1 0.72 a
Hypertension 6 4.4% 27 5.4% 0.8 0.82 a
Preeclampsia 1 0.7% 8 1.6% 0.5 0.69 a
Cigarette smoking 30 22.0% 143 28.6% 0.7 0.16 a
Methadon use 5 3.7% 8 1.6% 2.3 0.17 a

a Chi-square test.

b Student's t-test. SD, standard deviation; IUGR, intrauterine growth restriction; BMI, body mass index.

Table 3 Multivariate logistic regression model.

  Risk of preterm birth Risk of IUGR
Variables OR 95% CI p-Value OR 95% CI p-Value
SUA 5.00 1.8–13.8 0.002 11.13 4.8–25.6 <0.001
BMI > 30 0.43 0.05–3.5 0.43 2.02 0.7–5.6 0.17
Diabetes 0.70 0.09–5.7 0.74 0.00 0.00–N.A. 0.99
Hypertension 3.35 0.7–16.4 0.14 4.56 1.3–16.4 0.02
Cigarette smoking 0.75 0.2–2.7 0.66 1.11 0.5–2.7 0.82

IUGR, intrauterine growth restriction; OR, Odds ratio; 95% CI, 95% confidence interval; SUA, single umbilical artery; BMI, body mass index; NA, not available.

Of the 136 cases of isolated SUA, 75 (55.1%) neonates were delivered vaginally and 62 (45.6%) neonates were delivered by cesarean section (primary cesarean section (n = 51); secondary cesarean section (n = 11)). Of the 11 cases of secondary cesarean section, 6 (6/136; 4.4%) neonates were delivered by an emergency cesarean section due to fetal distress. In the SUA cohort in total 9 patients were delivered before 34 weeks. Of these, 3 patients were delivered vaginally and 6 by cesarean section. Indications for the very preterm deliveries were premature rupture of membrane (n = 6), spontaneous preterm labor (n = 2) and IUGR with fetal distress (n = 1), respectively. In the control group we observed a vaginal delivery rate of 70.8%. 29.2% were delivered by cesarean section, with a 2.7% cesarean section rate due to fetal distress. No case of IUFD or neonatal mortality was observed in the study population.

Comment

The aim of this study was to estimate the risk of IUGR, SGA and very preterm birth, associated with the finding of isolated SUA on second-trimester ultrasound using a robust, prospectively obtained database. Using a large retrospective cohort of patients, our study demonstrates that the finding of isolated SUA on second-trimester ultrasound is associated with an increased risk for IUGR, SGA fetuses and very preterm birth. The incidence of these adverse pregnancy outcomes was significantly higher than in the 3VC group, even after controlling for potential confounders affecting adverse pregnancy outcome. Using multivariate analysis, we observed a 5-fold risk for very preterm delivery and a 11-fold risk of IUGR compared to a 3VC control group. Our findings are in accordance with previous reports of Khalil [10] , Gornall et al. [11] , Rinehart et al. [12] and Hua et al. [3] , who demonstrated that the presence of an isolated SUA was associated with a poorer perinatal outcome as compared with a 3VC cohort. The authors reported IUGR rates between 20% and 50%, respectively[3], [11], and [12]. The higher prevalence of IUGR or SGA neonates has been related to a possible reduction in cytoplasmatic mass caused by malnutrition, rather than the total cell reduction that is usually seen in malformed fetuses with an early IUGR [13] . The incidence of IUGR in our cohort (15.4%) was lower than the rates previously reported, which may be due to the low-risk nature of our patient population, including only fetuses without congenital malformations or known chromosomal anomalies. Other researchers did not find an increased risk of IUGR in SUA pregnancies. Three recent case control studies showed no significant difference in neonatal outcome when SUA is found without other congenital anomalies and the authors suggested that routine serial ultrasound for fetal growth is not warranted in the presence of isolated SUA[4], [8], and [9]. However, the study of Predanic et al. has only limited power since 57 of 141 pregnancies were excluded because the diagnosis of SUA was not verified after delivery [4] . The study of Wiegand and co-workers [9] lacks data about birth weight and newborn examination and the article of Bombrys et al. [8] has been criticized for demographic differences between the comparison cohorts [3] . One might argue that the incidence of prematurity and lower birth weight found in the SUA cohort could be influenced by iatrogenic preterm deliveries. As our data could show none of the very preterm deliveries in the SUA cohort was iatrogenic due to isolated SUA. All cases had additional underlying indications for vaginal delivery or cesarean section such as PROM, breech presentation and/or preterm labor.

The presence of an isolated SUA has also been associated with increased rates of perinatal mortality [15] . In our study population, no case of IUFD or perinatal mortality has been observed. The rate of secondary cesarean section deliveries was 8.1% with a rate of 4.4% emergency cesarean section deliveries due to fetal distress, which is lower than the 19% reported by Gornall et al. [11] . The higher rate, as reported by Gornall et al. may be explained by the study's heterogenous patient population, including a composite of fetuses with congenital anomalies and multiple pregnancies.

Doppler flow measurements in isolated SUA did not predict adverse neonatal outcome, since 21 fetuses developed IUGR and pathologic Doppler values of uterine and umbilical artery were only observed in 4 and 2 cases, respectively. These findings are consistent with previously published data, where Doppler flow indices were within normal ranges[16] and [17], in cases of isolated and non-isolated SUA. Other authors however describe abnormal umbilical artery Dopplers in up to 30% of fetuses [18] , showing a higher amount of growth restriction, complex malformations, or chromosomal abnormalities in these cases.

Strengths of this study include our prospectively maintained perinatal database from which robust clinical data including obstetrical history, maternal demographic data, pregnancy outcome and neonatal outcome data was extracted. Our large sample size of isolated SUA allowed us to estimate the relationship between isolated SUA and multiple outcomes of interest. Limitations of our study include its retrospective study design and the fact that not all patients in the cohort underwent invasive aneuploidy testing. However, none of the neonates with isolated SUA had any dysmorphic features on postnatal examination by a neonatologist. Therefore, cytogenetic studies to exclude aneuploidy were not warranted. Additionally we do not have a histopathologic confirmation of SUA and as previously reported, even in expert hands, the false positive diagnosis of a two-vessel cord may be made[19] and [20]. However, a recent study by Lamberti et al. [21] , who compared the ultrasound diagnosis of a two-vessel cord with postnatal histopathology, reported a sensitivity and specificity of 86% and 99%, respectively for the ultrasound diagnosis of SUA in the second trimester.

Conclusion

In conclusion, our study demonstrates that finding of isolated SUA is associated with an increased risk for IUGR, SGA and very preterm birth. Using multivariate analysis, we observed that the association between isolated SUA and adverse pregnancy outcome persists even when other risk factors are excluded from the analysis. The information gained from this study may be useful for patient counseling and may also provide important information for developing appropriate antenatal management strategies.

Acknowledgements

We state that there are no financial or other relationships that might lead to a conflict of interest.

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Footnotes

a Medical University of Vienna, Department of Obstetrics and Gynecology, Division of Obstetrics and Feto-maternal Medicine, Austria

b Medical University of Vienna, Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Austria

lowast Corresponding author at: Medical University of Vienna, Department of Obstetrics and Gynecology, Waehringer Guertel 18 20, 1090 Vienna, Austria. Tel.: +43 1 40400 2821; fax: +43 1 40400 2862.