European Journal of Obstetrics & Gynecology and Reproductive Biology 147 (2009) 33–36
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Cardiac troponin T as a biochemical marker of cardiac dysfunction and ductus venosus Doppler velocimetry Roseli Mieko Yamamoto Nomura *, Fa´bio Roberto Cabar, Verbeˆnia Nunes Costa, Seizo Miyadahira, Marcelo Zugaib Department of Obstetrics and Gynecology, Faculty of Medicine, University of Sa˜o Paulo, Brazil
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 February 2009 Received in revised form 25 May 2009 Accepted 30 June 2009
Objectives: The aim of this study was to determine the correlation between ductus venosus (DV) Doppler velocimetry and fetal cardiac troponin T (cTnT). Study design: Between March 2007 and March 2008, 89 high-risk pregnancies were prospectively studied. All patients delivered by cesarean section and the Doppler exams were performed on the same day. Multiple regression included the following variables: maternal age, parity, hypertension, diabetes, gestational age at delivery, umbilical artery (UA) S/D ratio, diagnosis of absent or reversed end-diastolic flow velocity (AREDV) in the UA, middle cerebral artery (MCA) pulsatility index (PI), and DV pulsatility index for veins (PIV). Immediately after delivery, UA blood samples were obtained for the measurement of pH and cTnT levels. Statistical analysis included the Kruskal–Wallis test and multiple regressions. Results: The results showed a cTnT concentration at birth >0.05 ng/ml in nine (81.8%) of AREDV cases, a proportion significantly higher than that observed in normal UA S/D ratio and UA S/D ratio >p95 with positive diastolic blood flow (7.7 and 23.1%, respectively, p < 0.001). A positive correlation was found between abnormal DV-PIV and elevated cTnT levels in the UA. Multiple regression identified DV-PIV and a diagnosis of AREDV as independent factors associated with abnormal fetal cTnT levels (p < 0.0001, F(2.86) = 63.5, R = 0.7722). Conclusion: DV-PIV was significantly correlated with fetal cTnT concentrations at delivery. AREDV and abnormal DV flow represent severe cardiac compromise, with increased systemic venous pressure, and a rise in right ventricular afterload, demonstrated by myocardial damage and elevated fetal cTnT. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Troponin T Doppler ultrasound Ductus venosus Fetal blood flow
1. Introduction The fetal cardiovascular system shows physiological responses to chronic hypoxia and intrauterine growth restriction. A marked change in redistribution of fetal cardiac output is observed as a protective mechanism to maintain oxygen supply to the most vital fetal organs. Blood flow to the myocardium and adrenal glands, as well as to the fetal brain, is increased [1]. However, further deterioration of placental function reduces fetal oxygenation and leads to fetal cardiac involvement. The results are reduced ventricular output, increased venous pressure, and abnormal ductus venosus hemodynamics [2,3]. In growth-restricted fetuses, left ventricular afterload is decreased due to centralization of the cerebral circulation and
* Corresponding author at: Department of Obstetrics and Gynecology, Faculdade de Medicina da USP, Av Dr Ene´as de Carvalho Aguiar 255, 10th Floor, Suite 10036, Sa˜o Paulo, SP, CEP 05403-000, Brazil. Tel.: +55 11 3069 6209; fax: +55 11 3069 8183. E-mail address:
[email protected] (R.M.Y. Nomura). 0301-2115/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2009.06.029
right ventricular afterload is increased due to systemic vasoconstriction and elevated placental resistance. This results in increased right ventricular end-diastolic pressure and reduced ejection, with atrial contraction producing a prominent pressure peak (a-wave) in the venous system, and explains how deteriorating fetal oxygenation progressively leads to abnormal ductus venosus Doppler velocimetry. In placental insufficiency and fetal growth restriction, ductus venosus abnormalities have been proposed as predictive parameters of acid–base status and neonatal outcome [4]. Fetuses with myocardial damage analyzed by echocardiography show signs of increased systemic venous pressure and elevated cardiac troponin T (cTnT) levels determined at birth [5]. In normal uncomplicated deliveries, neonatal troponin T concentrations showed no clinically significant increase, but neonatal troponin T levels were increased when complications were associated with abnormal fetal umbilical venous return (pulsations in the umbilical vein) [6]. In adults, cTnT is the most sensitive biochemical marker of myocardial damage and elevated serum concentrations may
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Table 1 Maternal characteristics of the studied groups according to umbilical artery Doppler velocimetry. Results
Group 1, normal UA-S/D (n = 65)
Group 2, abnormal UA-S/D (n = 13)
Group 3, AREDV (n = 11)
p
Maternal age (years) Nulliparity Hypertension Diabetes mellitus
31.0 (6.9) 16 (24.6%) 27 (41.5%) 12 (18.5%)
28.2 (8.7) 8 (61.6%) 6 (46.2%) 2 (15.4%)
31.0 (8.0) 4 (36.4%) 11 (100%) 1 (9.1%)
0.432 0.03a 0.002a 0.736
Values are the mean (S.D.) or n (%). UA-S/D: systolic/diastolic ratio in the umbilical artery; AREDV: absent or reversed end-diastolic flow velocity in the umbilical artery. a Chi-square test.
suggest poor clinical outcome [7,8]. In the third trimester of gestation, the upper limits of cTnT are similar to those found in the newborn, with 90th and 95th percentiles of 0.034 and 0.05 ng/ml as reported by Baum et al. [9] and Clark et al. [10], respectively. Troponin T is one of the three subunits (troponin T, I and C) of the troponin complex. This regulatory protein interacts with actin and myosin to determine cardiac muscle contraction. The relative amount of the adult cTnT isoform increases significantly around the time of birth. A rabbit model study showed that this increase is more prominent in the left than in the right ventricles and is influenced by adrenergic stimulation and stress in the cardiovascular system during development [11]. The aim of the present study was to investigate the association between changes in ductus venosus Doppler velocimetry and myocardial cell injury in compromised fetuses with placental insufficiency, and to identify elevated levels of fetal cTnT at birth. 2. Subjects and methods Eighty-nine high-risk pregnancies evaluated between March 2007 and March 2008 were included in this cross-sectional study. The local Research Ethics Committee approved the research protocol and all women gave written informed consent. Inclusion criteria were singleton pregnancies, intact membranes, absence of fetal congenital or chromosomal abnormalities, and an indication for cesarean section delivery. In all women, gestational age was determined based on the last menstrual period and by ultrasonography performed before 20 weeks of gestation. Immediately after delivery, umbilical artery blood samples were collected for the measurement of pH and cTnT. Serum cTnT concentration was measured with commercially available enzyme-linked immunosorbent assay kits (Enzym-test Troponin-T, Roche Diagnostics, Mannheim, Germany) according to manufacturer instructions. The monoclonal antibodies used are highly specific for cTnT. In adults, the decisional level for myocardial damage is >0.05 ng/ml, and the reported 95th percentile for cTnT in healthy term newborns is 0.05 ng/ml. Acidemia at birth was defined as an umbilical artery pH below 7.20. Maternal hypertensive disorders were classified according to the guidelines of the American College of Obstetricians and Gynecologists [12]. Fifteen mothers had pre-eclampsia, 13 had severe pre-eclampsia, and 17 had chronic hypertension. Twelve mothers presented gestational diabetes and four pregnancies were complicated by pregestational diabetes. Doppler sonographic exams were performed with a real-time ultrasound apparatus (Envisor, Philips) equipped with a 3.5-MHz curved-array transducer using pulsed and color Doppler options. The high pass filter was set at the minimum. The size of the sample volume was adapted to the vessel diameter. All recordings used for analysis were obtained in the absence of fetal body and breathing movements and at a heart rate of 120–160 bpm. The angle of insonation was always kept below 308. The umbilical artery blood velocity waveforms were recorded from a part of the cord near its insertion into the placenta. The fetal
middle cerebral artery (MCA) was identified in the following manner: the circle of Willis was located in the fetal head at the level of the cerebral peduncles using color Doppler mode. The MCA was observed passing anteriorly to the peduncles, close to the greater wing of the sphenoid bone, with the angle of insonation being close to zero. The sample volume was placed approximately 1 cm from the beginning of the vessel from the circle of Willis. Ductus venosus blood velocity was recorded in the distal narrow central part, in an oblique transverse section. Doppler ultrasound exams were performed up to 12 h before delivery. Three consecutive cardiac cycles were obtained and the mean values were calculated and used for analysis. The systolic/diastolic (S/D) ratio and pulsatility index (PI) in the umbilical artery, and pulsatility index for veins (PIV) of the ductus venosus were calculated. Study groups were as follows: group 1 consisted of 65 fetuses with a normal umbilical artery Doppler S/D ratio according to local reference ranges for normal pregnancy. Group 2 consisted of 13 fetuses with increased placental resistance (umbilical artery S/D ratio >p95) and positive diastolic blood flow in the umbilical artery. Group 3 consisted of 11 fetuses with absent or reversed end-diastolic flow velocity (AREDV) in the umbilical arteries. Maternal and perinatal data of the groups are shown in Table 1. Data were analyzed using the Statistica for Windows program (Release 4.3, Statsoft, Inc. 1993) and are reported as the median and range. Statistical analysis was performed using the nonparametric Kruskal–Wallis test for comparisons between the three groups. Categorical data were compared using the chi-square test. Spearman’s rank test was used to show the correlation between umbilical cord cTnT concentrations and ductus venosus PIV values. Multiple regressions were performed using a stepwise forward procedure to identify independent variables related to elevated cTnT levels. The level of significance was set at p < 0.05 for all tests. 3. Results Eighty-nine high-risk pregnant women met the study criteria. All women delivered by pre-labor cesarean section. Umbilical artery, MCA and ductus venosus blood velocity were successfully recorded for all pregnancies. Gestational age at delivery, birth weight, and the 1st minute Apgar score were significantly lower in group 3 than in groups 1 and 2. The frequency of diabetes mellitus was similar in all groups studied. The occurrence of hypertensive disorders was associated with the AREDV group. The results of the Doppler exams are shown in Table 2. In group 3, cTnT concentrations at birth were >0.05 ng/ml in nine (81.8%) cases, a proportion significantly higher than that observed in groups 1 and 2 (p < 0.001). Acidemia at birth was more frequent in group 3 (eight cases, 72.7%) when compared with groups 1 and 2 (p < 0.01). Multiple regression analysis was performed to differentiate the independent effect of the variables determining elevated cTnT levels (>0.05 ng/ml). The following nine variables were included in the model: maternal age, parity, presence of arterial hypertension,
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Table 2 Perinatal outcome, Doppler results and cardiac troponin T concentration at delivery according to umbilical artery Doppler velocimetry. Results
Group 1, normal UA-S/D (n = 65)
Group 2, abnormal UA-S/D (n = 13)
Group 3, AREDV (n = 11)
p
GA at delivery (weeks) UA-PI MCA-PI DV-PIV UA Ph UA pH < 7.2 Birth weight (g) 1st min Apgar score 0.05
38 (30–40) 0.87 (0.56–1.28) 1.60 (1.02–2.33) 0.64 (0.39–0.98) 7.25 (7.02–7.35) 14 (21.5%) 3075 (1130–4410) 4 (6.2%) 0.01 (0.01–0.21) 5 (7.7%)
36 (27–39) 1.58 (1.5–1.96) 1.21 (0.84–1.9) 0.81 (0.54–1.2) 7.23 (7.08–7.30) 3 (23.1%) 1875 (820–3470) 3 (23.1%) 0.02 (0.01–0.08) 3 (23.1%)
30 (26–34) 2.6 (2.14–4.27) 0.97 (0.83–1.13) 1.1 (0.62–3.56) 7.18 (7.08–7.26) 8 (72.7%) 870 (490–1840) 5 (45.5%) 0.16 (0.03–0.26) 9 (81.8%)
