Fetuses With Trisomy 21 Having Conflicting Findings on Antenatal Testing for Fetal Well-being

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1 Case Series Fetuses With Trisomy 21 Having Conflicting Findings on Antenatal Testing for Fetal Well-being Geoffrey Wong, MD, Deborah Levine, MD Objective. This series reports 3 cases with conflicting antenatal sonographic findings: intrauterine growth restriction, absent or reversed end-diastolic flow in umbilical artery Doppler imaging, and reassuring biophysical test results. Methods. We conducted a retrospective review of medical records. Results. Three fetuses had intrauterine growth restriction and absent or reversed end-diastolic flow in umbilical artery Doppler studies, but the biophysical test results and amniotic fluid volume assessment were normal. We found no other signs of fetal jeopardy from placental insufficiency. In these cases, trisomy 21 was established after birth by karyotyping. Ventricular septal defects and aortic regurgitation were noted in 2 of the 3 affected fetuses. Conclusions. When there is an unusual combination of antenatal sonographic findings such as presented here, fetal cardiac abnormalities and aneuploidy should be considered. Key words: Doppler waveform; fetal anomalies; fetal growth restriction; trisomy 21; umbilical artery. Abbreviations IUGR, intrauterine growth restriction Received January 4, 2005, from the Departments of Obstetrics and Gynecology (G.W., D.L.) and Radiology (D.L.), Beth Israel Deaconess Medical Center, Boston, Massachusetts USA. Revision requested January 24, Revised manuscript accepted for publication July 20, Address correspondence to Geoffrey Wong, MD, Tufts-New England Medical Center, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, 750 Washington St, Boston, MA USA. gwong@tufts-nemc.org Intrauterine growth restriction (IUGR) is associated with increased perinatal morbidity and mortality. Although disturbance of fetal growth can be caused by many different factors, placental insufficiency, whether it is primary or secondary to a maternal condition, is the most common cause of IUGR. 1 Umbilical cord Doppler velocimetry has been used in conjunction with other traditional methods, such as nonstress tests and biophysical profiles, to assess fetal well-being and help determine management options. 2 Absent end-diastolic flow in the umbilical artery Doppler examination is often attributed to abnormal placental vasculature and increased resistance to blood flow. 3,4 An umbilical artery Doppler waveform showing abnormalities in a fetus with IUGR raises concerns about the risk of fetal death or neonatal complications and often prompts obstetric intervention. This series reports 3 fetuses with trisomy 21 who had IUGR and absent to reversed end-diastolic flow in umbilical artery Doppler flow studies. Other signs of placental insufficiency such as oligohydramnios and abnormal biophysical profiles were not present by the American Institute of Ultrasound in Medicine J Ultrasound Med 2005; 24: /05/$3.50

2 Conflicting Findings for Fetuses With Trisomy 21 Case Descriptions Case 1 A 41-year-old primigravida in good health was pregnant with dizygotic twins through in vitro fertilization. Amniocentesis was declined. A fetal anatomic survey performed at 18 weeks gestation showed no abnormalities. At a routine follow-up scan at 28 weeks gestation, the growth rate of twin A was normal, but twin B was growth restricted, with an estimated fetal weight at less than the 10th percentile. Twin B also had absent end-diastolic flow on a Doppler study of the umbilical artery. The result of biophysical profile testing, including amniotic fluid volume, was 10/10 (normal) for both twins. Antenatal steroids were given to accelerate fetal lung maturation in case early delivery was necessary. Twice-weekly fetal testing was instituted. The results of the biophysical test remained normal. A cesarean delivery was performed at 33 weeks gestation because of the continuing lag in fetal growth and persistent absent enddiastolic flow in twin B. Twin A, male, weighed 1958 g (50th percentile for gestational age), 5 with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Twin B, male, weighed 1455 g (5th percentile for gestational age) 5 and had Apgar scores of 6 and 7 at 1 and 5 minutes, respectively. The neonatal physical examination of twin B showed poor tone, abnormal facial features, low-set ears, and simian creases, which raised the possibility of trisomy 21. The diagnosis was established by chromosomal study. Because a cardiac murmur was not heard, a cardiac scan was not performed during the initial hospitalization; unfortunately, further information was not available as a result of lack of follow-up. Case 2 A 38-year-old primigravida with a singleton pregnancy achieved through in vitro fertilization was referred for assessment at 37 weeks gestation for a lagging symphseal-fundal height measurement. The patient had declined biochemical screening and amniocentesis for prenatal diagnosis of aneuploidy. Fetal biometric measurements showed IUGR with an estimated fetal weight at less than the 10th percentile. The umbilical artery Doppler study showed reversed end-diastolic flow. Biophysical profile testing was 10/10 (normal). Labor was induced, and a female neonate was delivered vaginally. The birth weight was 2072 g (<5th percentile for gestational age). 6 The Apgar scores were 6 and 7 at 1 and 5 minutes, respectively. Cord gas values were normal. The placenta weight was 243 g (normal term placental weight is g). 7 No placental infarction or histopathologic feature commonly associated with severe IUGR was found. The neonate had stigmata of trisomy 21 and poor tone. The chromosomal study confirmed the diagnosis of trisomy 21. A ventricular septal defect and mild aortic regurgitation were noted in the neonatal echocardiogram. Case 3 A 34-year-old woman, gravida 3, para 1, spontaneous aborta 1 was seen at 32 weeks gestation for a lagging symphseal-fundal height measurement. The patient had abnormal triple-marker screen results at 16 weeks, placing the risk for trisomy 21 at 1:160. She opted only for an ultrasound examination at 18 weeks. When no sonographic stigma of trisomy 21 were apparent, she declined amniocentesis. At 32 weeks gestation, the clinical diagnosis of IUGR was corroborated by ultrasound examination, showing an estimated fetal weight at less than the 10th percentile. The umbilical artery Doppler examination revealed absent diastolic flow. The biophysical profile assessment was 10/10 (normal). Structurally, ventricular septal defects as well as mild tricuspid and aortic regurgitation were noted. The patient was followed with fetal testing twice a week. At 37 weeks gestation, she delivered a male neonate who weighed 2186 g (<5th percentile for gestational age). 6 Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. Cord gas values were normal. The placenta weighed 257 g (normal term placental weight is g). 7 No infarction or prominent histopathologic or pathologic findings were found in the placenta. Karyotype studies of a fetal blood sample showed trisomy 21. Antenatal cardiac findings were confirmed by a neonatal echocardiogram. In all 3 cases, the patients medical histories did not indicate risk factors for IUGR, and there were no complications during pregnancy associated with IUGR. Results of laboratory tests for infections, antiphospholipid syndromes, and inherited thrombophilia were negative. Karyotyping was not performed on the placentas J Ultrasound Med 2005; 24:

3 Wong and Levine Discussion Chromosomal abnormalities are the cause of IUGR in 10% to 19% of cases. 8 Although most fetuses with aneuploidy and severe IUGR have readily detectable sonographic anomalies, fetuses affected by trisomy 21 often show no obvious abnormalities on antenatal structural surveys. 9 Fetuses with trisomy 21 are usually affected only mildly by IUGR. 10 In each of the 3 cases reported here, there was marked IUGR with birth weight at less than the 5th percentile. There was also absent and reversed end-diastolic flow in the umbilical artery Doppler studies. The combination of findings of IUGR and abnormal results of umbilical artery Doppler velocimetry usually points to placental insufficiency as the cause of the growth restriction. Increased placental resistance from abnormal placental vasculature is commonly cited as the explanation for absent or reversed end-diastolic flow in an umbilical artery Doppler study: the increased resistance interferes with the forward flow of the fetal blood during the diastolic phase. 3,4 Rochelson et al 11 reported quantitative changes in the placental vasculature in pregnancies affected by autosomy trisomy and discussed the role of those changes in producing IUGR and Doppler studies showing abnormalities in those pregnancies. Although in our case series the placenta cannot be ruled out as the cause of the IUGR and the umbilical artery Doppler studies that showed abnormalities, there were no prominent histopathologic findings in the placentas commonly associated with severe IUGR. Antepartum biophysical testing for fetal well-being showed no abnormalities. Oligohydramnios, a common finding with placental insufficiency, was not present. The 2 neonates that were delivered vaginally tolerated the stress of labor well and were born with normal Apgar scores and umbilical cord gas values. We hypothesize that the abnormal flow pattern can result from an upstream problem: specifically, the pump function of the fetal heart. Cardiac dysfunction apparent on Doppler examination has been reported in growth-restricted fetuses and in placental insufficiency. 12,13 Structural cardiac abnormalities can also produce abnormal findings in umbilical artery velocimetry. 14 Cardiac malformations are common in trisomy 21. The most common cardiac malformation associated with trisomy 21 is a ventricular septal defect, but valvular dysfunction has been reported as well. 15 In both cases reported here in which postnatal echocardiograms were available, aortic regurgitation was noted. The decreased forward flow of fetal blood in the fetal aorta during the diastolic phase may explain why there was absent or reversed end-diastolic flow in the umbilical artery Doppler examinations in these cases. To our knowledge, the impact of aortic regurgitation on umbilical artery Doppler waveforms has not been addressed in the literature (a PubMed search was performed with the following key words: aortic insufficiency, aortic regurgitation, and umbilical artery Doppler). It is possible that cardiac and hemodynamic dysfunctions that are manifested as abnormalities in Doppler velocimetry are common in fetuses with aneuploidy. Wenstrom et al 16 reported 4 cases with absent end-diastolic flow in umbilical artery Doppler studies in fetuses with chromosomal abnormalities. Two of these were fetuses with trisomy 18 who died in utero within 1 week of the Doppler examination that showed abnormalities. One had a trisomy 21 mosaic and IUGR and weighed 2600 g when delivered at 38.5 weeks after the abnormal flow was noted during Doppler imaging. The last case was a fetus with autosomal inversion and multiple fetal anomalies; the pregnancy was terminated electively. Wu et al 17 reported absent end-diastolic flow during the umbilical artery Doppler examination in 2 fetuses with triploidy. In a series by Rizzo et al 18 of 192 fetuses with absent end-diastolic flow in umbilical artery Doppler studies, 16 had abnormal karyotypes: 2 were triploid; 9 had trisomy 18; 4 had IUGR and trisomy 21; and 1 had an autosomal deletion. Rizzo et al 18 attributed the growth restriction and the Doppler study results showing abnormalities in their series to placental insufficiency; however, there was no information about the results of conventional antenatal testing for fetal well-being or histopathologic examination of the placentas to support this thesis. There was also no information on examinations conducted either antenatally or after birth to rule out a cardiac abnormality as a possible cause of the findings. Recent studies have noted absent end-diastolic flow in the ductus venosus when fetuses with aneuploidy were scanned at 10 to 14 weeks. 19,20 These studies raised the possibility of using such scans as early screens for chromosomal abnor- J Ultrasound Med 2005; 24:

4 Conflicting Findings for Fetuses With Trisomy 21 malities. Long-term data about how pregnancies with these early findings of Doppler velocimetry showing abnormalities in the fetuses turn out are currently not available because many of these pregnancies are terminated electively after the diagnosis of aneuploidy has been established. It can be speculated that these fetuses might be those who would die in utero if the pregnancies were to continue. They also might be at greater risk for severe IUGR if they were to survive. Doppler velocimetry scans showing abnormalities might persist if these fetuses are scanned during the later part of the pregnancy, as reported in this case series. In the literature that we reviewed, the aneuploidies noted in fetuses with IUGR and the umbilical artery Doppler study results showing abnormalities were diverse. We hypothesize that the underlying causes of some of those abnormal Doppler study results could be related to structural or functional cardiac anomalies. Although placental pathologic features are the most common causes of IUGR and abnormal results of umbilical artery Doppler examinations, an incongruous combination of IUGR, absent end-diastolic flow in umbilical artery Doppler examinations, and normal results of amniotic fluid volume and reassuring biophysical profile testing should prompt a detailed investigation to rule out cardiac and chromosomal abnormalities. References 1. Baschat AA, Hecher K. Fetal growth restriction due to placental disease. Semin Perinatol 2004; 28: Vergani P, Andreotti C, Roncaglia N, et al. Doppler predictor of adverse neonatal outcome in growth restricted fetus at 34 weeks gestation or beyond. Am J Obstet Gynecol 2003; 189: Krebs C, Macara LM, Leiser R, Bowman AW, Greer IA, Kingdom JC. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstet Gynecol 1996; 175: Salafia CM, Pezzullo JC, Minior VK, Divon MY. Placental pathology of absent and reversed enddiastolic flow in growth-restricted fetuses. Obstet Gynecol 1997; 90: Min SJ, Luke B, Gillespie B, et al. Birth weight references for twins. Am J Obstet Gynecol 2000; 182: Doubilet PM, Benson CB, Nadel AS, Ringer SA. Improved birth weight table for neonates developed from gestations dated by early ultrasonography. J Ultrasound Med 1997; 16: Benirschke K, Kaufmann P. Pathology of the Human Placenta. 4th ed. New York, NY: Springer-Verlag; 2000: Snijders RJ, Sherrod C, Gosden CM, Nicolaides KH. Fetal growth retardation: associated malformations and chromosomal abnormalities. Am J Obstet Gynecol 1993; 168: Benaceraff B. Ultrasound evaluation of chromosomal abnormalities. In: Callen PW (ed). Ultrasonography in Obstetrics and Gynecology. 4th ed. Philadelphia, PA: WB Saunders Co; 2000: Kurjak A, Kirkinen P. Ultrasonic growth pattern of fetuses with chromosomal aberrations. Acta Obstet Gynecol Scand 1982; 61: Rochelson B, Kaplan C, Cuzman 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: Rizzo G, Capponi A, Rinaldo D, Arduini D, Romanini C. Ventricular ejection force in growth retarded fetuses. Ultrasound Obstet Gynecol 1995; 5: Makikallio K, Vuolteenaho O, Jouppila P, Rasanen J. Ultrasonographic and biochemical markers of human fetal cardiac dysfunction in placental insufficiency. Circulation 2002; 105: Al-Gazali W, Chapman MG, Chita SK, Crawford DC, Allan LD. Doppler assessment of umbilical artery blood flow for the prediction of outcome in fetal cardiac abnormality. Br J Obstet Gynaecol 1987; 94: Goldhaber SZ, Brown WD, Sutton MG. High frequency of mitral valve prolapse and aortic regurgitation among asymptomatic adults with Down s syndrome. JAMA 1987; 258: Wenstrom KD, Weiner CP, Williamson RA. Diverse maternal and fetal pathology associated with absent diastolic flow in the umbilical artery of high-risk fetuses. Obstet Gynecol 1991; 77: J Ultrasound Med 2005; 24:

5 Wong and Levine 17. Wu RT, Shyu MK, Lee CN, et al. Sonographic manifestation and Doppler blood flow study in fetal triploidy syndrome: report of two cases. J Ultrasound Med 1995; 14: 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: Matias A, Montenegro N. Ductus venosus blood flow in chromosomally abnormal fetuses at 11 to 14 weeks gestation. Semin Perinatol 2001; 25: Mavrides E, Sairam S, Hollis B, Thilaganathan B. Screening for aneuploidy in the first trimester by assessment of blood flow in the ductus venosus. Br J Obstet Gynecol 2002; 109: J Ultrasound Med 2005; 24: