Original Paper Published online: June 24, 2015
Fetal Diagn Ther DOI: 10.1159/000433431
Increased Umbilical Artery Pulsatility Index in Third-Trimester Fetuses with Trisomy 21 Philipp Wagner a Jiri Sonek b Markus Hoopmann a Harald Abele a Sara Brucker a Karl Oliver Kagan a
a
Department of Obstetrics and Gynaecology, University of Tuebingen, Germany; b Fetal Medicine Foundation USA, and Division of Maternal Fetal Medicine, Wright State University, Dayton, Ohio, USA
Key Words Trisomy 21 · Umbilical artery · Pulsatility index · Doppler
tile. Conclusion: In half of the third-trimester fetuses with trisomy 21, the resistance in the UA is increased – even in the absence of placental insufficiency. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 1015–3837/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/fdt
Introduction
Algorithms for screening and diagnosing trisomy 21 have become highly efficient. With the current change towards cell-free fetal DNA testing, the detection rate for trisomy 21 approaches 99% and the number of invasive procedures to achieve this detection has diminished dramatically [1–3]. However, there is a significant proportion of pregnancies where the diagnosis of trisomy 21 does not end up in termination [4–6]; therefore, it is important to optimize the care of those affected fetuses where a live birth is the desired outcome. It is recognized that, on average, fetuses with trisomy 21 are smaller than euploid fetuses [7]. In 1 study including 182 neonates with trisomy 21 born at 38 weeks’ gestation, the average birth weights for males and females were 3,100 and 2,900 g respectively [8]. This is significantly less than what is expected for euploid neonates. There are essentially Prof. Dr. Karl Oliver Kagan University of Tuebingen Calwerstrasse 7 DE–72076 Tübingen (Germany) E-Mail KOKagan @ gmx.de
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Abstract Objective: To examine the umbilical arterial Doppler flow patterns in late third-trimester fetuses with trisomy 21. Methods: This is a retrospective study on fetuses with trisomy 21 that were evaluated after 33 weeks’ gestation at the Department of Obstetrics and Gynaecology of the University of Tuebingen, Germany. The umbilical and the middle cerebral artery (UA and ACM) pulsatility index (PI) measurements and the abdominal circumference were transformed into z-values. Results: Forty-two fetuses met the study criteria. The mean gestational age at the time of the first and the second visit was 35.0 and 36.6 weeks, respectively. The mean UA PI was 1.31 and 1.38, which corresponds to z-values of 2.20 and 2.70. In 24 (57.1%) cases, both PI measurements were above the 95th centile. A linear regression analysis demonstrated that the mean of both UA PI was not dependent on the abdominal circumference or on any other examined maternal and pregnancy characteristics. The mean ACM PI at the first and the second visit was 1.62 and 1.48, respectively, corresponding to mean z-values of –0.59 and –0.75, and in none of the cases was it below the 5th cen-
Methods A search of an electronic database was performed to identify all fetuses with trisomy 21 that were evaluated at the Department of Obstetrics and Gynaecology of the University of Tuebingen, Germany, between 2006 and 2014. To reduce random effects, our study included only those cases where at least 2 UA Doppler examinations were performed after 33 weeks’ gestation. In cases of more numerous examinations, only the results of the first 2 evaluations were used. In the vast majority, the abnormal karyotype was known throughout the course of the pregnancy and the parents opted against the termination of pregnancy. In 4 cases, the diagnosis was made postnatally. This information was added to the database shortly after birth. In all cases, we collected data on maternal and gestational age at the time of the 2 examinations. We also recorded the abdominal circumference measurement and the presence or absence of a car-
2
Fetal Diagn Ther DOI: 10.1159/000433431
diac defect, gastrointestinal obstruction, and polyhydramnios. The latter was defined as deepest pool of more than 8 cm [10]. The Doppler measurements that were recorded included the UA PI, and, if available, PI of the middle cerebral artery (MCA). Statistical Methods The UA and MCA PI measurements were transformed into zvalues according to the normal ranges published by Acharya et al. [11] and Baschat and Gembruch [12], respectively. The abdominal circumference was transformed into z-values according to the normal curve of Hadlock et al. [13]. Fetuses were classified as small for gestational age if the abdominal circumference was below the 10th centile. Differences were either tested by a t test (after confirming the normal distribution of the data using Kolmogorov-Smirnoff test) or a χ2 test. Regression analysis was used to examine whether there is a significant relationship between the UA and ACM PI and the maternal and pregnancy covariates (p ≤ 0.05). The analysis was performed with IBM SPSS Version 22 (Armonk, New York, N.Y., USA).
Results
The search of the database revealed 42 pregnancies with trisomy 21 that met the study criteria. The mean gestational age at the time of the first and the second visit was 35.0 weeks and 36.6 weeks, respectively. Thus, the average interval between both visits was 1.6 weeks. The mean gestational age at delivery was 37.3 weeks. The mean birth weight was 2,764 g, corresponding to the 26.8 centile. The mean arterial pH after birth was 7.29 and the lowest arterial pH in our study population was 7.18. Further characteristics of the study population are shown in table 1. Twenty-two (52.4%) fetuses had an abdominal circumference measurement that was below the 10th centile. These cases were grouped as small for gestational age cases. Half of the fetuses had a cardiac defect (18 cases with septal defects, 2 tetralogy of Fallot, 1 double outlet right ventricle) and gastrointestinal obstruction was found in 9 (21.4%) cases. Eleven (26.2%) pregnancies were complicated by polyhydramnios. Overall, the mean UA PI was 1.31 (SD 0.36) at the first examination and 1.38 (SD 0.57) at the second examination. This corresponds to z-values of 2.20 and 2.70 (SD 1.71 and 2.70), respectively. The mean difference between the z-values of both measurements was 0.50 (SD 1.94), which is not significantly different from 0 (t test; p = 0.104). End-diastolic flow was present in all but 1 examination. In 26 (61.9%) cases, the PI measurement was above the 95th centile in at least 1 of the 2 examinations, and in 24 (57.1%) of cases, both PI measurements were above the 95th centile (fig. 1). Wagner/Sonek/Hoopmann/Abele/ Brucker/Kagan
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2 possible explanations for this finding. One is that fetuses with trisomy 21 have a diminished growth potential compared to euploid fetuses, and the second one is that the placental performance of pregnancies affected by trisomy 21 is suboptimal. Certainly, the small size of fetuses with trisomy 21 may be due to the combination of these 2 factors. A clinical measurement that can be used to distinguish between placental insufficiency and diminished growth potential is to assess the placental vascular resistance by pulsed Doppler sonography of the umbilical artery (UA). There is some evidence that UA Doppler abnormalities are more prevalent in pregnancies affected by trisomy 21. However, only a few studies have focused on this issue. In a more recent study, Flöck et al. [9] examined 281 fetuses with trisomy 21 after 20 weeks’ gestation. It was found that umbilical artery measurements were abnormal in about 40% of the cases. Furthermore, the proportion of abnormal measurements increased with gestational age changing from 35% at around 20 weeks to 65% after 35 weeks’ gestation. However, while the study included 203 fetuses that were evaluated prior to 25 weeks’ gestation, only 11 fetuses were examined at or after 35 weeks’ gestation. The fact that fetuses affected by trisomy 21 have an increased intrauterine death rate is well recognized. The exact reason for this increase is not certain, but it may be related to placental dysfunction. In order to optimize the clinical utilization of tests such as UA Doppler sonography, it is important to understand how the presence of trisomy 21 affects the results of these tests. Therefore, we designed a retrospective study to examine the arterial Doppler flow patterns in late third-trimester fetuses with trisomy 21 and to assess relevant pregnancy characteristics that may carry an impact on the pulsatility index (PI) in these cases.
Table 1. Characteristics of the study
population
Maternal age, years Gestational age at the time of the first visit, weeks Gestational age at the time of the second visit, weeks Interval between first and second visit, weeks Gestational age at delivery, weeks Birth weight, g Birth weight, centiles Arterial pH at birth Third APGAR value 10 min after birth
35.0 (18.3 – 45.6 ) 35.0 (33.0 – 40.0) 36.6 (33.3 – 40.3) 1.6 (0.3 – 4.9) 37.3 (36.6 – 38.3) 2,764 (1,400 – 4,500) 26.8 (2.0 – 98.0) 7.29 (7.18 – 7.38) 9.0 (7.0 – 10.0)
Values are represented as mean (range).
Table 2. Linear regression analysis to assess significant covariates
7.0
influencing the mean UA PI measurement expressed as z-value
Maternal age (years) Gestational age (weeks) Cardiac defect (yes vs. no) GI Obstruction (yes vs. no) Polyhydramnios (yes vs. no) Mean abdominal circumference (z-value)
OR (95% CI)
6.0
p
–0.04 (–0.15 – 0.07) 0.12 (–0.24 – 0.48) 0.99 (–0.26 – 2.24) 0.05 (–1.52 – 1.62) –0.25 (–1.72 – 1.22)
0.480 0.504 0.116 0.949 0.730
–0.04 (–0.14 – 0.06)
0.479
5.0 4.0 UA PI (z-values)
Covariate
3.0 2.0 1.0 0 –1.0
In the small for gestational age group, there were 12 (54.6%) cases where both UA PI measurements were above the 95th centile. The appropriate for gestational age group also included 12 (60.0%) fetuses that had 2 increased PI measurements (χ2; p = 0.127). A linear regression analysis demonstrated that the mean value of both UA PI measurements was not dependent on the abdominal circumference or on any of the other examined maternal and pregnancy characteristics (table 2; fig. 2). Two MCA measurements that were obtained at the same time as the UA measurements were available in a subset of 22 cases. Mean PI at the first and second visits were 1.62 (SD 0.26) and 1.48 (SD 0.38) corresponding to mean z-values of –0.59 (SD 0.92) and –0.75 (SD 1.02), respectively. We did not find any cases where both measurements were below the 5th centile. There was no significant correlation between the UA and MCA PI measurements [linear regression: MCA PI z-values: OR –1.20 (95% CI –2.58 to 0.18), p = 0.085]. Figure 3 shows the distribution of UA and MCA PI measurements in the average and small for gestational age fetuses. There was also no significant correlation between the MCA/UA ratio and the AC [OR –1.07 (95% CI –0.71 to 0.37), p = 0.514].
Comparison with Previous Studies Our results are consistent with the few and generally older previous studies that can be found in the literature. In a report that included 3 cases of third-trimester fetuses with trisomy 21, Wong and Levine [14] noted an absent or reversed end-diastolic UA flow without any other signs of placental insufficiency and in the presence
Increased UA PI in Third-Trimester Fetuses with Trisomy 21
Fetal Diagn Ther DOI: 10.1159/000433431
–2.0
Visit 1
Visit 2
Fig. 1. Distribution of the UA PI at the first and second visit.
Discussion
3
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Main Findings of this Study This third-trimester study suggests that fetuses with trisomy 21 have a UA PI that is higher than in the normal population. The increase appears to be independent of the size of the abdominal circumference, the MCA PI, and of other maternal and pregnancy characteristics.
2.0
6.0
1.5
4.0
1.0 MCA PI (z-values)
UA PI (z-values)
8.0
2.0 0 –2.0
0.5 0 –0.5
–4.0
–1.0
–6.0
–1.5
–8.0
–2.0 –8.0
–6.0
–4.0
–2.0
0
2.0
4.0
6.0
8.0
Abdominal circumference (z-values)
Fig. 2. Distribution of the UA PI and abdominal circumference.
SGA AGA
0
2.0
4.0
6.0
8.0
10.0
UA (z-values)
Fig. 3. Distribution of the UA and MCA PI in small and average
for gestational age (SGA and AGA) fetuses.
4
Fetal Diagn Ther DOI: 10.1159/000433431
the placental vasculature may be responsible for the increased vascular resistance and subsequent increase of the UA PI. The utility of UA PI measurements in the identification of aneuploidy in the first trimester and their relationship to nuchal translucency (NT) measurements have also been investigated. Brown et al. [18] examined a group of 458 fetuses between 10 and 14 weeks’ gestation, which included 21 cases of trisomy 21. They found no association between the UA PI and the fetal karyotype or the NT measurement. Similar results were reported by Zoppi et al. [19] who examined the UA PI in 121 first trimester fetuses with an increased NT, including 20 with trisomy 21. A pattern of increasing prevalence of abnormal Doppler findings in fetuses with trisomy 21 as the gestational age increases was also noted in the abovementioned study by Flöck et al. In this study, approximately one third of mid second-trimester fetuses with trisomy 21 had a UA PI measurement that was above the 95th percentile. This number increased to about two thirds of fetuses when examined after 30 weeks’ gestation [9]. Rizzo et al. [20] took a different approach to investigating the relationship between abnormal UA Doppler and aneuploidy. This study looked at 192 fetuses with an absent end-diastolic flow. An abnormal karyotype was Wagner/Sonek/Hoopmann/Abele/ Brucker/Kagan
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of a reassuring biophysical profile. Floeck et al. [9] also examined the UA PI in a small series of third-trimester fetuses with trisomy 21. Between 30 and 34 weeks’ gestation, UA PI was above the 95th centile in 74% of the 27 cases and in 64% of the 11 cases between 34 weeks and term, respectively. In a study performed in 1990, Rochelson et al. [15] evaluated the umbilical artery blood flow in 10 affected pregnancies in the late third trimester. They found that the end-diastolic flow was absent in half of the pregnancies. The overall average birth weight in these cases was about 2,900 g. They also performed histologic examinations of 17 third-trimester placentas in pregnancies with trisomy 21. It was noted that the number of muscular arteries was smaller and the ratio of these arteries to the number of villi was reduced in comparison to the euploid group. Qureshi et al. [16] examined 6 placentas of trisomy 21 pregnancies. They noted an increased presence of irregular hypovascular villi and focal areas of hypervascularity. Kuhlmann et al. [17] examined the placental vasculature in 14 chromosomal abnormalities terminated between 18 and 23 weeks’ gestation. Four of those were trisomy 21 cases and 2 trisomy 18 placentas. There were fewer vessels in the affected cases, especially the number of small muscular arteries was reduced. These changes in
found in only about 10% of the fetuses. However, the majority of the aneuploid fetuses had trisomy 18, and the Dopplers were obtained prior to 30 weeks’ gestation. Implications for Practice Our results should help improve antenatal care of fetuses with trisomy 21. Specifically, we noted that in the third trimester, an increased resistance in the UA can be found in about half of pregnancies affected by trisomy 21. In the absence of any other abnormal findings indicating placental insufficiency, this can be considered as a normal variant. Recognition of this fact may reduce the chance of an unnecessary early delivery. Regardless of the karyotype, the initial fetal Doppler abnormality in a third-trimester growth-restricted fetus is expected to occur in the MCA rather than the UA [21, 22]. In our study, the MCA resistance was slightly lower
than expected but was not below the 5th centile in any of our cases. In addition, we did not observe any correlation between MCA PI and the abdominal circumference. However, we acknowledge that our series is too small to draw any definite conclusion regarding the utility of MCA Doppler in monitoring fetuses with trisomy 21.
Conclusion
In about half of the fetuses with trisomy 21, the resistance in the UA is increased in the third trimester. The proportion with abnormal findings rises throughout the pregnancy. An increased resistance should trigger a careful examination and search for other signs of placental insufficiency, but in the absence, it is more likely to be a normal variant.
References
Increased UA PI in Third-Trimester Fetuses with Trisomy 21
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ke RJBJ: Prevalence, neonatal characteristics, and first-year mortality of Down syndrome: a national study. J Pediatr 2008; 152: 15–19. Flöck A, Remig I, Müller A, Nadal J, Berg C, Gembruch U, et al: Conflicting umbilical artery Doppler findings in fetuses with trisomy 21. Arch Gynecol Obstet 2015:1–5. Magann EF, Doherty DA, Chauhan SP, Busch FWJ, Mecacci F, Morrison JC: How well do the amniotic fluid index and single deepest pocket indices (below the 3rd and 5th and above the 95th and 97th percentiles) predict oligohydramnios and hydramnios? Am J Obstet Gynecol 2004;190:164–169. Acharya G, Wilsgaard T, Berntsen GKR, Maltau JM, Kiserud T: Reference ranges for serial measurements of umbilical artery Doppler indices in the second half of pregnancy. Am J Obstet Gynecol 2005;192:937–944. Baschat AA, Gembruch U: The cerebroplacental Doppler ratio revisited. Ultrasound Obstet Gynecol 2003;21:124–127. Hadlock FP, Harrist RB, Carpenter RJ, Deter RL, Park SK: Sonographic estimation of fetal weight. The value of femur length in addition to head and abdomen measurements. Radiology 1984;150:535–540. Wong G, Levine D: Fetuses with trisomy 21 having conflicting findings on antenatal testing for fetal well-being. J Ultrasound Med 2005;24:1541–1545. Rochelson B, Kaplan C, Guzman E, Arato M, Hansen K, Trunca C: A quantitative analysis of placental vasculature in the third-trimester fetus with autosomal trisomy. Obstet Gynecol 1990;75:59–63.
Fetal Diagn Ther DOI: 10.1159/000433431
16 Qureshi F, Jacques SM, Johnson MP, Hume RF, Kramer RL, Yaron Y, et al: Trisomy 21 placentas: histopathological and immunohistochemical findings using proliferating cell nuclear antigen. Fetal Diagn Ther 1997; 12: 210–215. 17 Kuhlmann RS, Werner AL, Abramowicz J, Warsof SL, Arrington J, Levy DL: Placental histology in fetuses between 18 and 23 weeks’ gestation with abnormal karyotype. Am J Obstet Gynecol 1990;163:1264–1270. 18 Brown R, Di Luzio L, Gomes C, Nicolaides KH: The umbilical artery pulsatility index in the first trimester: is there an association with increased nuchal translucency or chromosomal abnormality? Ultrasound Obstet Gynecol 1998;12:244–247. 19 Zoppi MA, Ibba RM, Putzolu M, Floris M, Monni G: First trimester umbilical artery pulsatility index in fetuses presenting enlarged nuchal translucency. Prenat Diagn 2000; 20: 701–704. 20 Rizzo G, Pietropolli A, Capponi A, Arduini D, Romanini C: Chromosomal abnormalities in fetuses with absent end-diastolic velocity in umbilical artery: analysis of risk factors for an abnormal karyotype. Am J Obstet Gynecol 1994;171:827–831. 21 Savchev S, Figueras F, Gratacós E: Survey on the current trends in managing intrauterine growth restriction. Fetal Diagn Ther 2014;36: 129–135. 22 Figueras F, Gratacós E: Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn Ther 2014;36:86– 98.
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1 Gil MM, Quezada MS, Revello R, Akolekar R, Nicolaides KH: Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 2015;45:249–266. 2 Gil MM, Akolekar R, Quezada MS, Bregant B, Nicolaides KH: Analysis of cell-free DNA in maternal blood in screening for aneuploidies: meta-analysis. Fetal Diagn Ther 2014;35:156– 173. 3 Gratacós E, Nicolaides K: Clinical perspective of cell-free DNA testing for fetal aneuploidies. Fetal Diagn Ther 2014;35:151–155. 4 Janvier A, Couture E, Deschenes M, Nadeau S, Barrington K, Lantos J: Health care professionals’ attitudes about pregnancy termination for different fetal anomalies. Paediatr Child Health 2012;17:e86–e88. 5 Siljee JE, Knegt AC, Knapen MFCM, Bekker MN, Visser GHA, Schielen PCJI: Positive predictive values for detection of trisomies 21, 18 and 13 and termination of pregnancy rates after referral for advanced maternal age, first trimester combined test or ultrasound abnormalities in a national screening programme (2007–2009). Prenat Diagn 2014;34:259–264. 6 Verweij EJJ, Oepkes D, de Boer MA: Changing attitudes towards termination of pregnancy for trisomy 21 with non-invasive prenatal trisomy testing: a population-based study in Dutch pregnant women. Prenat Diagn 2013; 33:397–399. 7 Stoll C, Alembik Y, Dott B, Roth MP: Study of Down syndrome in 238,942 consecutive births. Ann Genet 1998;41:44–51. 8 Weijerman ME, van Furth AM, Vonk Noordegraaf A, van Wouwe JP, Broers CJM, Gem-
Fetal Diagn Ther DOI: 10.1159/000433431
Increased Umbilical Artery Pulsatility Index in Third-Trimester Fetuses with Trisomy 21 Philipp Wagner a Jiri Sonek b Markus Hoopmann a Harald Abele a Sara Brucker a Karl Oliver Kagan a
a
Department of Obstetrics and Gynaecology, University of Tuebingen, Germany; b Fetal Medicine Foundation USA, and Division of Maternal Fetal Medicine, Wright State University, Dayton, Ohio, USA
Key Words Trisomy 21 · Umbilical artery · Pulsatility index · Doppler
tile. Conclusion: In half of the third-trimester fetuses with trisomy 21, the resistance in the UA is increased – even in the absence of placental insufficiency. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 1015–3837/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/fdt
Introduction
Algorithms for screening and diagnosing trisomy 21 have become highly efficient. With the current change towards cell-free fetal DNA testing, the detection rate for trisomy 21 approaches 99% and the number of invasive procedures to achieve this detection has diminished dramatically [1–3]. However, there is a significant proportion of pregnancies where the diagnosis of trisomy 21 does not end up in termination [4–6]; therefore, it is important to optimize the care of those affected fetuses where a live birth is the desired outcome. It is recognized that, on average, fetuses with trisomy 21 are smaller than euploid fetuses [7]. In 1 study including 182 neonates with trisomy 21 born at 38 weeks’ gestation, the average birth weights for males and females were 3,100 and 2,900 g respectively [8]. This is significantly less than what is expected for euploid neonates. There are essentially Prof. Dr. Karl Oliver Kagan University of Tuebingen Calwerstrasse 7 DE–72076 Tübingen (Germany) E-Mail KOKagan @ gmx.de
Downloaded by: UCONN Storrs 198.143.38.1 - 1/27/2016 2:47:36 AM
Abstract Objective: To examine the umbilical arterial Doppler flow patterns in late third-trimester fetuses with trisomy 21. Methods: This is a retrospective study on fetuses with trisomy 21 that were evaluated after 33 weeks’ gestation at the Department of Obstetrics and Gynaecology of the University of Tuebingen, Germany. The umbilical and the middle cerebral artery (UA and ACM) pulsatility index (PI) measurements and the abdominal circumference were transformed into z-values. Results: Forty-two fetuses met the study criteria. The mean gestational age at the time of the first and the second visit was 35.0 and 36.6 weeks, respectively. The mean UA PI was 1.31 and 1.38, which corresponds to z-values of 2.20 and 2.70. In 24 (57.1%) cases, both PI measurements were above the 95th centile. A linear regression analysis demonstrated that the mean of both UA PI was not dependent on the abdominal circumference or on any other examined maternal and pregnancy characteristics. The mean ACM PI at the first and the second visit was 1.62 and 1.48, respectively, corresponding to mean z-values of –0.59 and –0.75, and in none of the cases was it below the 5th cen-
Methods A search of an electronic database was performed to identify all fetuses with trisomy 21 that were evaluated at the Department of Obstetrics and Gynaecology of the University of Tuebingen, Germany, between 2006 and 2014. To reduce random effects, our study included only those cases where at least 2 UA Doppler examinations were performed after 33 weeks’ gestation. In cases of more numerous examinations, only the results of the first 2 evaluations were used. In the vast majority, the abnormal karyotype was known throughout the course of the pregnancy and the parents opted against the termination of pregnancy. In 4 cases, the diagnosis was made postnatally. This information was added to the database shortly after birth. In all cases, we collected data on maternal and gestational age at the time of the 2 examinations. We also recorded the abdominal circumference measurement and the presence or absence of a car-
2
Fetal Diagn Ther DOI: 10.1159/000433431
diac defect, gastrointestinal obstruction, and polyhydramnios. The latter was defined as deepest pool of more than 8 cm [10]. The Doppler measurements that were recorded included the UA PI, and, if available, PI of the middle cerebral artery (MCA). Statistical Methods The UA and MCA PI measurements were transformed into zvalues according to the normal ranges published by Acharya et al. [11] and Baschat and Gembruch [12], respectively. The abdominal circumference was transformed into z-values according to the normal curve of Hadlock et al. [13]. Fetuses were classified as small for gestational age if the abdominal circumference was below the 10th centile. Differences were either tested by a t test (after confirming the normal distribution of the data using Kolmogorov-Smirnoff test) or a χ2 test. Regression analysis was used to examine whether there is a significant relationship between the UA and ACM PI and the maternal and pregnancy covariates (p ≤ 0.05). The analysis was performed with IBM SPSS Version 22 (Armonk, New York, N.Y., USA).
Results
The search of the database revealed 42 pregnancies with trisomy 21 that met the study criteria. The mean gestational age at the time of the first and the second visit was 35.0 weeks and 36.6 weeks, respectively. Thus, the average interval between both visits was 1.6 weeks. The mean gestational age at delivery was 37.3 weeks. The mean birth weight was 2,764 g, corresponding to the 26.8 centile. The mean arterial pH after birth was 7.29 and the lowest arterial pH in our study population was 7.18. Further characteristics of the study population are shown in table 1. Twenty-two (52.4%) fetuses had an abdominal circumference measurement that was below the 10th centile. These cases were grouped as small for gestational age cases. Half of the fetuses had a cardiac defect (18 cases with septal defects, 2 tetralogy of Fallot, 1 double outlet right ventricle) and gastrointestinal obstruction was found in 9 (21.4%) cases. Eleven (26.2%) pregnancies were complicated by polyhydramnios. Overall, the mean UA PI was 1.31 (SD 0.36) at the first examination and 1.38 (SD 0.57) at the second examination. This corresponds to z-values of 2.20 and 2.70 (SD 1.71 and 2.70), respectively. The mean difference between the z-values of both measurements was 0.50 (SD 1.94), which is not significantly different from 0 (t test; p = 0.104). End-diastolic flow was present in all but 1 examination. In 26 (61.9%) cases, the PI measurement was above the 95th centile in at least 1 of the 2 examinations, and in 24 (57.1%) of cases, both PI measurements were above the 95th centile (fig. 1). Wagner/Sonek/Hoopmann/Abele/ Brucker/Kagan
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2 possible explanations for this finding. One is that fetuses with trisomy 21 have a diminished growth potential compared to euploid fetuses, and the second one is that the placental performance of pregnancies affected by trisomy 21 is suboptimal. Certainly, the small size of fetuses with trisomy 21 may be due to the combination of these 2 factors. A clinical measurement that can be used to distinguish between placental insufficiency and diminished growth potential is to assess the placental vascular resistance by pulsed Doppler sonography of the umbilical artery (UA). There is some evidence that UA Doppler abnormalities are more prevalent in pregnancies affected by trisomy 21. However, only a few studies have focused on this issue. In a more recent study, Flöck et al. [9] examined 281 fetuses with trisomy 21 after 20 weeks’ gestation. It was found that umbilical artery measurements were abnormal in about 40% of the cases. Furthermore, the proportion of abnormal measurements increased with gestational age changing from 35% at around 20 weeks to 65% after 35 weeks’ gestation. However, while the study included 203 fetuses that were evaluated prior to 25 weeks’ gestation, only 11 fetuses were examined at or after 35 weeks’ gestation. The fact that fetuses affected by trisomy 21 have an increased intrauterine death rate is well recognized. The exact reason for this increase is not certain, but it may be related to placental dysfunction. In order to optimize the clinical utilization of tests such as UA Doppler sonography, it is important to understand how the presence of trisomy 21 affects the results of these tests. Therefore, we designed a retrospective study to examine the arterial Doppler flow patterns in late third-trimester fetuses with trisomy 21 and to assess relevant pregnancy characteristics that may carry an impact on the pulsatility index (PI) in these cases.
Table 1. Characteristics of the study
population
Maternal age, years Gestational age at the time of the first visit, weeks Gestational age at the time of the second visit, weeks Interval between first and second visit, weeks Gestational age at delivery, weeks Birth weight, g Birth weight, centiles Arterial pH at birth Third APGAR value 10 min after birth
35.0 (18.3 – 45.6 ) 35.0 (33.0 – 40.0) 36.6 (33.3 – 40.3) 1.6 (0.3 – 4.9) 37.3 (36.6 – 38.3) 2,764 (1,400 – 4,500) 26.8 (2.0 – 98.0) 7.29 (7.18 – 7.38) 9.0 (7.0 – 10.0)
Values are represented as mean (range).
Table 2. Linear regression analysis to assess significant covariates
7.0
influencing the mean UA PI measurement expressed as z-value
Maternal age (years) Gestational age (weeks) Cardiac defect (yes vs. no) GI Obstruction (yes vs. no) Polyhydramnios (yes vs. no) Mean abdominal circumference (z-value)
OR (95% CI)
6.0
p
–0.04 (–0.15 – 0.07) 0.12 (–0.24 – 0.48) 0.99 (–0.26 – 2.24) 0.05 (–1.52 – 1.62) –0.25 (–1.72 – 1.22)
0.480 0.504 0.116 0.949 0.730
–0.04 (–0.14 – 0.06)
0.479
5.0 4.0 UA PI (z-values)
Covariate
3.0 2.0 1.0 0 –1.0
In the small for gestational age group, there were 12 (54.6%) cases where both UA PI measurements were above the 95th centile. The appropriate for gestational age group also included 12 (60.0%) fetuses that had 2 increased PI measurements (χ2; p = 0.127). A linear regression analysis demonstrated that the mean value of both UA PI measurements was not dependent on the abdominal circumference or on any of the other examined maternal and pregnancy characteristics (table 2; fig. 2). Two MCA measurements that were obtained at the same time as the UA measurements were available in a subset of 22 cases. Mean PI at the first and second visits were 1.62 (SD 0.26) and 1.48 (SD 0.38) corresponding to mean z-values of –0.59 (SD 0.92) and –0.75 (SD 1.02), respectively. We did not find any cases where both measurements were below the 5th centile. There was no significant correlation between the UA and MCA PI measurements [linear regression: MCA PI z-values: OR –1.20 (95% CI –2.58 to 0.18), p = 0.085]. Figure 3 shows the distribution of UA and MCA PI measurements in the average and small for gestational age fetuses. There was also no significant correlation between the MCA/UA ratio and the AC [OR –1.07 (95% CI –0.71 to 0.37), p = 0.514].
Comparison with Previous Studies Our results are consistent with the few and generally older previous studies that can be found in the literature. In a report that included 3 cases of third-trimester fetuses with trisomy 21, Wong and Levine [14] noted an absent or reversed end-diastolic UA flow without any other signs of placental insufficiency and in the presence
Increased UA PI in Third-Trimester Fetuses with Trisomy 21
Fetal Diagn Ther DOI: 10.1159/000433431
–2.0
Visit 1
Visit 2
Fig. 1. Distribution of the UA PI at the first and second visit.
Discussion
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Main Findings of this Study This third-trimester study suggests that fetuses with trisomy 21 have a UA PI that is higher than in the normal population. The increase appears to be independent of the size of the abdominal circumference, the MCA PI, and of other maternal and pregnancy characteristics.
2.0
6.0
1.5
4.0
1.0 MCA PI (z-values)
UA PI (z-values)
8.0
2.0 0 –2.0
0.5 0 –0.5
–4.0
–1.0
–6.0
–1.5
–8.0
–2.0 –8.0
–6.0
–4.0
–2.0
0
2.0
4.0
6.0
8.0
Abdominal circumference (z-values)
Fig. 2. Distribution of the UA PI and abdominal circumference.
SGA AGA
0
2.0
4.0
6.0
8.0
10.0
UA (z-values)
Fig. 3. Distribution of the UA and MCA PI in small and average
for gestational age (SGA and AGA) fetuses.
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Fetal Diagn Ther DOI: 10.1159/000433431
the placental vasculature may be responsible for the increased vascular resistance and subsequent increase of the UA PI. The utility of UA PI measurements in the identification of aneuploidy in the first trimester and their relationship to nuchal translucency (NT) measurements have also been investigated. Brown et al. [18] examined a group of 458 fetuses between 10 and 14 weeks’ gestation, which included 21 cases of trisomy 21. They found no association between the UA PI and the fetal karyotype or the NT measurement. Similar results were reported by Zoppi et al. [19] who examined the UA PI in 121 first trimester fetuses with an increased NT, including 20 with trisomy 21. A pattern of increasing prevalence of abnormal Doppler findings in fetuses with trisomy 21 as the gestational age increases was also noted in the abovementioned study by Flöck et al. In this study, approximately one third of mid second-trimester fetuses with trisomy 21 had a UA PI measurement that was above the 95th percentile. This number increased to about two thirds of fetuses when examined after 30 weeks’ gestation [9]. Rizzo et al. [20] took a different approach to investigating the relationship between abnormal UA Doppler and aneuploidy. This study looked at 192 fetuses with an absent end-diastolic flow. An abnormal karyotype was Wagner/Sonek/Hoopmann/Abele/ Brucker/Kagan
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of a reassuring biophysical profile. Floeck et al. [9] also examined the UA PI in a small series of third-trimester fetuses with trisomy 21. Between 30 and 34 weeks’ gestation, UA PI was above the 95th centile in 74% of the 27 cases and in 64% of the 11 cases between 34 weeks and term, respectively. In a study performed in 1990, Rochelson et al. [15] evaluated the umbilical artery blood flow in 10 affected pregnancies in the late third trimester. They found that the end-diastolic flow was absent in half of the pregnancies. The overall average birth weight in these cases was about 2,900 g. They also performed histologic examinations of 17 third-trimester placentas in pregnancies with trisomy 21. It was noted that the number of muscular arteries was smaller and the ratio of these arteries to the number of villi was reduced in comparison to the euploid group. Qureshi et al. [16] examined 6 placentas of trisomy 21 pregnancies. They noted an increased presence of irregular hypovascular villi and focal areas of hypervascularity. Kuhlmann et al. [17] examined the placental vasculature in 14 chromosomal abnormalities terminated between 18 and 23 weeks’ gestation. Four of those were trisomy 21 cases and 2 trisomy 18 placentas. There were fewer vessels in the affected cases, especially the number of small muscular arteries was reduced. These changes in
found in only about 10% of the fetuses. However, the majority of the aneuploid fetuses had trisomy 18, and the Dopplers were obtained prior to 30 weeks’ gestation. Implications for Practice Our results should help improve antenatal care of fetuses with trisomy 21. Specifically, we noted that in the third trimester, an increased resistance in the UA can be found in about half of pregnancies affected by trisomy 21. In the absence of any other abnormal findings indicating placental insufficiency, this can be considered as a normal variant. Recognition of this fact may reduce the chance of an unnecessary early delivery. Regardless of the karyotype, the initial fetal Doppler abnormality in a third-trimester growth-restricted fetus is expected to occur in the MCA rather than the UA [21, 22]. In our study, the MCA resistance was slightly lower
than expected but was not below the 5th centile in any of our cases. In addition, we did not observe any correlation between MCA PI and the abdominal circumference. However, we acknowledge that our series is too small to draw any definite conclusion regarding the utility of MCA Doppler in monitoring fetuses with trisomy 21.
Conclusion
In about half of the fetuses with trisomy 21, the resistance in the UA is increased in the third trimester. The proportion with abnormal findings rises throughout the pregnancy. An increased resistance should trigger a careful examination and search for other signs of placental insufficiency, but in the absence, it is more likely to be a normal variant.
References
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