Abnormal Ductus Venosus Flow With Increased Nuchal Translucency


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Abnormal Ductus Venosus Flow With Increased Nuchal Translucency

  1. 1. CME Article Abnormal Ductus Venosus Flow in First-Trimester Fetuses With Increased Nuchal Translucency Relationship With the Type of Cardiac Defect? Yolanda M. de Mooij, MD, Monique C. Haak, MD, PhD, Margot M. Bartelings, MD, PhD, Jos W. Twisk, MA, PhD, Adriana Gittenberger-de Groot, PhD, John M. G. van Vugt, MD, PhD, Mireille N. Bekker, MD, PhD Objective. The purpose of this study was to evaluate ductus venosus flow velocities and a possible relationship with the type of cardiac defect in fetuses with increased nuchal translucency (NT). Methods. Seventy-two fetuses with normal NT and 137 fetuses with increased NT (>95th percentile) were evaluated. The ductus venosus pulsatility index for veins (PIV), late diastolic velocity (velocity dur- ing atrial contraction [a-V]), and intracardiac velocities were evaluated. In cases of pregnancy termina- tion, a postmortem examination was performed. Cardiac defects were grouped into septal defects, left and right inflow obstruction, left and right outflow obstruction, and other defects. Data were evalu- ated by multilevel analysis. Results. A cardiac defect was found in 45 fetuses with increased NT. Fetuses with increased NT showed a higher ductus venosus PIV and a lower a-V compared to fetuses with nor- mal NT (P < .05). Within the group of fetuses with increased NT, a higher PIV and a lower a-V were found in cases with a cardiac defect compared to cases with a normal heart (P < .001). No differences in PIV and a-V were found between the types of cardiac defects. Intracardiac velocities showed no dif- ferences between fetuses with normal and increased NT, irrespective of the presence of a cardiac defect. Conclusions. Ductus venosus flow velocities in fetuses with increased NT are not related to a certain type of cardiac defect. This indicates that the altered ductus venosus flow velocities found in fetuses with increased NT cannot be explained by cardiac failure due to a specific altered cardiac anatomy. Key words: cardiac defect; Doppler sonography; ductus venosus; nuchal translucency; sonography. Abbreviations a-V, velocity during atrial contraction; JLS, jugular lym- phatic sac; NT, nuchal translucency; PIV, pulsatility index for veins S Received December 28, 2009, from the Departments onographic measurement of nuchal translucen- of Obstetrics and Gynecology (Y.M.d.M., M.C.H., J.M.G.v.V., M.N.B.) and Clinical Epidemiology and cy (NT) in human fetuses between 11 and 14 Biostatistics (J.W.T.), VU University Medical Center, weeks’ gestation is a widely used screening Amsterdam, the Netherlands; and Department of Anatomy and Embryology, Leiden University Medical method to identify chromosomal abnormali- 1,2 Center, Leiden, the Netherlands (M.M.B., A.G.-d.G.). ties. Increased NT is also associated with structural Revision requested January 25, 2010. Revised anomalies such as cardiac defects and several genetic manuscript accepted for publication March 8, 2010. Address correspondence to Yolanda M. de Mooij, syndromes.3 MD, Department of Obstetrics and Gynecology, VU Several mechanisms, such as a disturbance in lymphat- University Medical Center, Suite PK6 -170, Postbus 7057, 1007-MB Amsterdam, the Netherlands. ic development, an altered extracellular matrix, and car- E-mail: ym.demooij@vumc.nl diac failure, have been proposed to play a role in the pathophysiologic mechanism of increased NT.4–9 Cardiac CME Article includes CME test failure has been suggested because of the high propor- © 2010 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 2010; 29:1051–1058 • 0278-4297/10/$3.50
  2. 2. Abnormal Ductus Venosus Flow With Increased Nuchal Translucency tion of cardiovascular malformations and abnor- Healthcare, Kretztechnik, Zipf, Austria; or 2–4 mal ductus venosus Doppler flow velocities in both MHz, HDI 5000; Philips Healthcare, Bothell, WA) euploid and aneuploid fetuses with increased according to the guidelines of the Fetal Medicine NT.4,5,10–13 It was hypothesized that a cardiac Foundation.14 defect could result in impaired cardiac function Flow velocity waveforms of the ductus venosus resulting in a lower velocity of the ductus veno- were obtained from a right ventral midsagittal sus and subsequently enlargement of the NT.4,12 plane of the fetal trunk during fetal quiescence. To our knowledge, however, no study has been Color flow was used to visualize the venous cir- performed to assess whether altered ductus culation. The pulsed Doppler gate (0.7–1.5 mm) venosus flow velocities in fetuses with increased was placed in the inlet of the ductus venosus NT are related to a specific type of cardiac defect where it originates from the umbilical vein. Care or anatomy. was taken to avoid contamination of the flow The goal of this study was to evaluate whether waveforms of the umbilical vein and inferior ductus venosus flow alterations in fetuses with vena cava.15 The interrogation angle was kept as increased NT could be explained by hemody- low as possible and always less than 60°. An aver- namic changes due to a certain type of cardiac age of 3 consecutive high-quality waveforms was defect. In addition, ductus venosus flow veloci- used to analyze the peak systolic velocity, late ties in relation to intracardiac velocities were diastolic velocity (velocity during atrial contrac- assessed. The hypothesis that increased NT is tion [a-V]), and time-averaged velocity. These caused by cardiac failure due to a certain type of variables were used to calculate the pulsatility cardiac defect was tested. index for veins (PIV = systolic velocity – a-V/time- averaged velocity). Materials and Methods To obtain flow velocity waveforms across the mitral and tricuspid valves, the pulsed Doppler Women referred to our hospital for tertiary care sample gate was placed just distal from the valves because of increased NT were asked to partici- in an apical 4-chamber view in the absence of pate in the study. A total of 135 singleton and 2 fetal movements. Adjustment was made for the bichorial twin pregnancies were examined. Two insonation angle, which never exceeded 40°. of these 137 fetuses were part of bichorial twins Peak flow velocities in early diastole (E wave) and of which only the fetuses with increased NT were late diastole with atrial contraction (A wave) were included. Increased NT was defined as NT above measured, and the E/A ratio was calculated. the 95th percentile. A control group of 73 fetuses Digital images of each examination were stored. with normal NT was created from women The cardiac defects were grouped into 6 cate- attending our hospital for first-trimester screen- gories according to the hemodynamic classifica- ing. All patients received written information and tion adapted from Atzei et al16: septal defects, left gave informed consent. The Medical Ethical inflow obstruction, right inflow obstruction, left Committee of VU University Medical Center outflow obstruction, right outflow obstruction, approved the study. and other defects. Where more than 1 of the cat- Gestational age was calculated on the basis of egories potentially applied, obstruction was the reported last menstrual period and adjusted given precedence over a septal defect.16 according to the crown-rump length if appropri- ate. After inclusion, sonographic examinations were performed weekly by 3 experienced sonog- Table 1. Examinations per Fetus (n = 209) raphers (Y.M.d.M., M.C.H., and M.N.B.) between Fetuses With Fetuses With 11 and 17 weeks’ gestation (Table 1). The number No. of Normal Increased of examinations differed because of different ges- Examinations NT (n = 72) NT (n = 137) tational ages at the initial scan and patients’ 1 0 59 cooperation. Nuchal translucency was measured 2 10 46 using a transabdominal probe (4–8 MHz, 3 49 27 Voluson 730 Expert series, Voluson E8; GE 4 13 5 1052 J Ultrasound Med 2010; 29:1051–1058
  3. 3. de Mooij et al Karyotyping was performed by chorionic villus left inflow obstruction, right inflow obstruction, sampling or amniocentesis. In case of termina- left outflow obstruction, right outflow obstruc- tion of the pregnancy, suction aspiration was tion, and other defects were used to create performed, or labor was induced. A postmortem groups. We analyzed whether Doppler flow mea- morphologic examination was performed if the surements of the compared groups differed sig- patient approved. The fetus or aspiration tissue nificantly in relation to advancing gestational was fixed in formalin 4%. Subsequently, a post- age. If necessary, a log transformation was mortem evaluation of the whole fetus or the fetal used to account for non-normality of the data. heart (in case of suction aspiration) was per- General estimating equation analysis was also formed using a dissection microscope. An exten- used to assess a possible relationship between sive sequential segmental analysis of the heart Doppler flow measurements and NT size (corre- was performed by an experienced cardiac mor- lation coefficient). The statistical significance phologist (M.M.B.). In ongoing pregnancies, a level was set at P = .05. second-trimester sonographic examination was performed in all cases. After delivery, the parents Results completed questionnaires concerning their neonate’s health. If necessary, medical records In total, 73 fetuses with normal NT and 137 fetus- were studied to gain additional information. es with increased NT were included in the study. The ductus venosus indices PIV and a-V and In the group of fetuses with normal NT, 1 patient intracardiac velocities of fetuses with normal was excluded from further analysis because of an and increased NT, with respect to the presence of intrauterine fetal death due to a fetal growth a heart defect, were compared. Within the group restriction at 28 weeks’ gestation. A postmortem of fetuses with increased NT, the ductus venosus examination revealed no abnormalities in this PIV and a-V and intracardiac velocities of case. Follow-up was complete, and in all 72 euploid and aneuploid fetuses were compared. cases, healthy neonates were born. The charac- Furthermore, within the group of fetuses with teristics of the 209 fetuses included are listed in cardiac defects, the ductus venosus PIV and a-V Table 2. and intracardiac velocities were assessed for the In cases of increased NT, invasive tests were different types of cardiac defects. offered but refused in 3 cases. In these cases, Data were studied using general estimating healthy neonates without dysmorphic features equation analysis (SPSS version 15.0; SPSS Inc, were born and were considered euploid. A nor- Chicago, IL). This method takes into account the mal karyotype was found in 83 of the 137 fetuses fact that the same patients are repeatedly mea- with increased NT (61%); 54 fetuses (39%) were sured and allows missing observations and irreg- aneuploid. Figure 1 shows the disposition of the ularly spaced time intervals. fetuses with increased NT included in the study. Variables indicating fetuses with normal NT, The presence or absence of a cardiac defect in fetuses with increased NT without a cardiac fetuses with increased NT was known by follow- defect, and fetuses with increased NT with a car- up after birth or postmortem examinations in diac defect were used to create groups. Within 118 of the 137 fetuses (86%). In 14 of the 137 the group of fetuses with increased NT and a car- cases (5%), heart morphologic features were only diac defect, variables indicating septal defects, assessed by prenatal sonography, and post- Table 2. Characteristics of the Fetuses With Normal and Increased NT at the First Sonographic Examination Normal NT (n = 72) Increased NT (n = 137) Characteristic Mean (SD) Range Mean (SD) Range Maternal age, years 34.4 (3.6) 26–41 33.5 (4.5) 21–44 Gestational age, wk + d 11 + 4 (0 + 3) 11 + 0–13 + 2 12 + 4 (0 + 5) 11 + 0–13 + 6 NT, mm 1.2 (0.4) 0.7–2.2 4.9 (2.4) 2.4–14.0 Crown-rump length, mm 54.0 (5.9) 41.9–72.5 61.7 (10.1) 41–84.4 J Ultrasound Med 2010; 29:1051–1058 1053
  4. 4. Abnormal Ductus Venosus Flow With Increased Nuchal Translucency mortem examinations were refused. In 7 of these mal NT (82%) and in 203 of the 251 examinations cases, a cardiac defect was suspected. The car- of fetuses with increased NT (81%). The ductus diovascular anomalies (n = 45) included septal venosus PIV was significantly higher in fetuses defects (n = 20, ventricular and atrioventricular), with increased NT compared to fetuses with left inflow obstruction (n = 5, hypoplastic left normal NT between 11 and 16 weeks’ gestation heart syndrome), left outflow obstruction (n = 8, (P < .05). Within the group of fetuses with coarctation of the aorta, aortic valve atresia, and increased NT, a significantly higher ductus veno- stenosis), right outflow obstruction (n = 5, tetralo- sus PIV was found in aneuploid fetuses com- gy of Fallot, pulmonary valve atresia, and stenosis), pared to euploid fetuses and in fetuses with a and other (n = 7, cardiomyopathy, polyvalvular dis- cardiac defect compared to fetuses with a nor- ease, and an aberrant right subclavian artery). mal heart (P < .001). No significant differences in the ductus venosus PIV were found between the Ductus Venosus Flow Velocities different types of cardiac defects (Figure 2). The ductus venosus was successfully assessed in Greater NT was associated with a higher ductus 181 of the 221 examinations of fetuses with nor- venosus PIV (r = 0.64; P < .001). Figure 1. Disposition of the 137 fetuses with increased NT included in the study. Cardiovascular anomalies (n = 45) included septal defects (n = 20), left outflow obstruction (n = 8), right outflow obstruction (n = 5), left inflow obstruction (n = 5), and other (n = 7). ‡Postmortem examinations were not possi- ble: selective reduction in twin pregnancy (n = 2). †Postmortem examinations were unsuccessful because of the absence of the fetal heart in the aspiration specimen (n = 2) and a severely damaged heart (n = 2). §Karyotype, 46,XY, der(18)t(3;18)(q27;p11.1). *Noonan syndrome was diagnosed postnatally on the basis of clinical symptoms; the infant died at 1 year. **Noonan syndrome confirmed with DNA analysis (n = 2). IUFD indicates intrauterine fetal death. 1054 J Ultrasound Med 2010; 29:1051–1058
  5. 5. de Mooij et al The ductus venosus a-V was significantly lower cant differences (data not shown). No relation- in fetuses with increased NT compared to fetus- ship between intracardiac flow velocities and NT es with normal NT (P < .001; Figure 3). Within the size was found. group of fetuses with increased NT, a significant- ly lower ductus venosus a-V was found in aneu- Discussion ploid fetuses compared to euploid fetuses and in fetuses with an abnormal heart compared to This study evaluated whether ductus venosus fetuses with a normal heart (P < .001). No signifi- flow alterations in fetuses with increased NT can cant differences in the ductus venosus a-V were be explained by hemodynamic changes due to a found between the different types of cardiac certain type of cardiac defect. In the group of defects (Figure 4). Greater NT was associated with fetuses with increased NT, those with a cardiac a lower ductus venosus a-V (r = –0.61; P < .001). defect showed a significantly higher PIV and a lower a-V of the ductus venosus. No significant Intracardiac Flow Velocities differences were found between the different In 187 of the 219 measurements of fetuses with types of cardiac defects. Previous reports also normal NT (85%), intracardiac flow velocity showed a relationship between altered ductus waveforms (tricuspid and mitral valves) could be venosus flow velocities in fetuses with increased recorded. In 168 (77%) of the 219 measurements NT and cardiac defects.12,13,17 However, to our of fetuses with increased NT, intracardiac flow knowledge, a study assessing increased NT and velocity waveforms could be obtained. No signifi- ductus venosus flow in relation to type of cardiac cant differences in the intracardiac velocities (E abnormalities has not been reported previously. wave, A wave, and E/A ratio) between fetuses Impaired cardiac function due to cardiac with normal and increased NT were found (data defects has been suggested to play a role in the not shown). Within the group of fetuses with development of increased NT.4,12 Abnormal duc- increased NT, no significant differences in intrac- tus venosus flow velocities could be the result of ardiac velocities were found between fetuses an increase in ventricular end-diastolic pressure with and without a cardiac defect. Within the due to impaired atrial contraction.4 Left and group of fetuses with increased NT, aneuploid right heart obstructions, for example, pulmonary fetuses showed significantly lower E and A waves valve stenosis, could result in an increase in right of the mitral and tricuspid valves compared to ventricular pressure and reversed flow in the the euploid fetuses (P < .05). The E/A ratio of the ductus venosus during atrial contraction. Hyett mitral and tricuspid valves did not show signifi- et al5 proposed that increased NT could be Figure 2. Mean ductus venosus PIV of fetuses with normal and increased NT with respect to the type of cardiac defect. GA indicates gestational age. J Ultrasound Med 2010; 29:1051–1058 1055
  6. 6. Abnormal Ductus Venosus Flow With Increased Nuchal Translucency A B Figure 3. Ductus venosus flow velocity waveforms showing normal flow and reversed flow during atrial contraction (a-V) in a fetus with normal NT (A) and a fetus with increased NT (B). A, Gestational age, 12 weeks; NT, 1.2 mm; normal heart; karyotype, 46,XX. B, Gestational age, 12 weeks 5 days; NT, 5.4 mm; myocardial hypertrophy (atria and ventricles); karyotype, 47,XX+21. Figure 4. Mean ductus venosus a-V of fetuses with normal and increased NT with respect to the type of cardiac defect. GA indicates gestational age. 1056 J Ultrasound Med 2010; 29:1051–1058
  7. 7. de Mooij et al explained by overperfusion of the head due to alterations found. Interestingly, a recent longitu- preferential blood flow through the head and dinal sonographic study by our group, investi- neck as a result of an obstruction of the aortic gating fetuses with increased NT and a distended arch. However, in our data, no significant differ- JLS, showed a higher jugular vein and ductus ences in the ductus venosus PIV between left and venosus PIV in those fetuses compared to fetuses right outflow obstructions and septal defects, for with normal NT.23 A disturbance in venous example, were found. Also, not all fetuses with endothelial differentiation was suggested as an increased NT and abnormal ductus venosus flow explanation for these findings. Previous morpho- waveforms had a diagnosis of a cardiac abnormal- logic studies of both fetuses with increased NT ity. Within the group of fetuses with increased NT, and mouse embryos with trisomy 16, an animal the aneuploid fetuses showed significantly lower E model for trisomy 21, showed abnormal and A waves compared to the euploid fetuses, endothelial differentiation of the jugular venous- which is in accordance with previous data from lymphatic system.24 Abnormal endothelial dif- our group.18 However, within this group of fetuses, ferentiation also has been reported to play a no significant differences in intracardiac velocities role in the development of cardiac defects.25,26 between fetuses with and without cardiac defects Altered endothelial differentiation could explain were shown. The left and right ventricle function the finding that altered ductus venosus flow was not diminished in fetuses with increased NT velocities in fetuses with increased NT are inde- because no differences in intracardiac velocities pendent of a specific type of cardiac defect. were shown between fetuses with normal and A broad range of abnormalities are associated increased NT. In addition, no other signs of car- with increased NT.1,3 One single explanation for diac failure such as pleural effusion and ascites the origin of increased NT is therefore not likely. were found in the fetuses with increased NT. Thus, A delay or disturbance in endothelial develop- the results of this study do not support the theory ment and differentiation could be a common that higher right ventricular pressure is responsi- process related to the lymphatic abnormalities, ble for the alterations in ductus venosus flow cardiac defects, and altered ductus venosus and velocities. A limitation of the study was the small jugular vein flow found in fetuses with increased sample size of the groups with cardiac defects. NT. We hypothesize that a disturbance in endothe- The fact that no relationship was found between lial differentiation can vary from delayed but cardiac defects that could influence the hemody- physiologic development to more disturbed namics and ductus venosus flow velocities indi- development. Aneuploid fetuses with increased cates that cardiac failure alone cannot explain the NT probably endure a more severe disturbance altered ductus venosus velocities and pathophys- in endothelial differentiation. iologic mechanism of increased NT. Ductus venosus flow has been suggested as an Another suggested explanation for increased additional marker in first-trimester screening for NT is a disturbance in lymphatic development. aneuploidy.11,13 Our study, however, showed that First-trimester fetuses with increased NT mor- greater NT was related to a higher PIV and a phologically show nuchal edema accompanied lower a-V of the ductus venosus. A recent study by a distended jugular lymphatic sac (JLS).19 by Maiz et al27 showed a similar association Lymphangiogenesis starts with the development between NT size and the a-V of the ductus veno- of the JLS, which normally reorganizes into lym- sus. In our opinion, this indicates that ductus phatic nodes after 10 weeks’ gestation.20–22 venosus flow is not an independent marker in Delayed reorganization of the JLS into lymph screening for aneuploidy. nodes could explain both the transient and In conclusion, we have shown that ductus regional character of increased NT. venosus flow velocities in fetuses with increased Because this study shows that altered ductus NT are not related to a certain type of cardiac venosus flow velocities are not related to a spe- defect. This indicates that the altered ductus cific type of cardiac defect such as outflow venosus flow velocities found in fetuses with an obstruction, we hypothesize that a mechanism increased NT cannot be explained by cardiac other than cardiac failure is responsible for the failure due to specific altered cardiac anatomy. J Ultrasound Med 2010; 29:1051–1058 1057
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