Objective
Intrauterine growth restricted (IUGR) fetuses experience cardiovascular remodeling that persists into infancy and has been related to cardiovascular outcomes in adulthood. Hypertension in infancy has been demonstrated to be a strong risk factor for later cardiovascular disease. Close monitoring together with dietary interventions have shown to improve cardiovascular health in hypertensive children; however, not all IUGR infants show increased blood pressure. We evaluated the potential of fetal echocardiography for predicting hypertension and arterial remodeling in 6-month-old IUGR infants.
Study Design
One hundred consecutive IUGR and 100 control fetuses were observed into infancy. Fetal assessment included perinatal Doppler imaging, cardiac morphometry, ejection fraction, cardiac output, isovolumic relaxation time (IVRT), tricuspid annular-plane systolic excursion (TAPSE), and tissue Doppler imaging. Infant hypertension and arterial remodeling were defined as mean blood pressure of >95th percentile together with aortic intima-media thickness of >75th percentile at 6 months of age. Odds ratio were obtained for fetal parameters that were associated with infant outcomes.
Results
Fetal TAPSE, right sphericity index, IVRT, and cerebroplacental ratio were the strongest predictors for postnatal vascular remodeling. A cardiovascular risk score that was based on fetal TAPSE, cerebroplacental ratio, right sphericity index, and IVRT was highly predictive of infant hypertension and arterial remodeling (area under the curve, 0.87; 95% confidence interval, 0.79–0.93; P < .001).
Conclusion
Fetal echocardiographic parameters identify a high-risk group within the IUGR fetuses who could be targeted for early screening of blood pressure and other cardiovascular risk factors and for promoting healthy diet and physical exercise.
Intrauterine growth restriction (IUGR) is defined as an estimated fetal weight below the 10th percentile for gestational age. Evidence from large epidemiologic studies has long suggested a strong association between IUGR and increased cardiovascular mortality rates in adulthood. Recent prospective studies have described that fetuses with IUGR have cardiac remodeling and dysfunction that persists into infancy in the form of remodeled hearts, hypertension, and increased intima-media thickness. Hypertension in childhood is a strong risk factor for later cardiovascular disease and is considered an indication for lifestyle modifications. Detection of IUGR may constitute an opportunity to apply preventive cardiovascular interventions from early life. However, IUGR may affect up to 5-10% of the whole population, and only a fraction will display the cardiovascular features described earlier during childhood. Therefore, personalized medicine approaches are required to allow selection of subjects who are at high risk.
Perinatal selection of cases that are at risk would allow an efficient approach to detect fetuses who may later benefit from early screening and intervention in infancy. Perinatal criteria that are used conventionally to establish the severity of IUGR, such as gestational age at onset or fetoplacental Doppler changes, have shown a weak association with postnatal cardiovascular findings. Thus, a remarkable proportion of fetuses with relatively benign forms of IUGR may still experience hypertension and cardiovascular remodeling in childhood. Fetal echocardiography is a potential and so far unexplored approach to achieve prenatal detection of cardiovascular remodeling that persists into childhood. Several functional and morphometric echocardiographic parameters show remarkable differences in IUGR with respect to normally grown fetuses. However, the relationship of these changes with cardiovascular findings in childhood has not been determined. It is unknown to what extent prenatal changes are only a direct reflection of fetal deterioration because of hypoxia and undernutrition that occurs in IUGR. In addition, events during the neonatal period might exert influences in later cardiovascular function.
We conducted a prospective cohort study that included 100 IUGR fetuses and 100 normally grown fetuses. Subjects were evaluated prenatally with comprehensive echocardiography and followed into 6 months of age to assess blood pressure and aortic intima-media thickness (aIMT). We evaluated the correlation of fetal echocardiographic parameters with postnatal cardiovascular features and explored whether a cardiovascular score was predictive of infant hypertension and arterial remodeling.
Materials and Methods
Study population
The study design was a prospective cohort study that included fetuses with IUGR and control subjects who were identified in utero and followed into infancy. The source population comprised women who were pregnant from April 2010 to September 2012 who attended the Department of Maternal–Fetal Medicine at Hospital Clínic in Barcelona, Spain. Pregnancies with structural/chromosomal anomalies, multiple pregnancies, or evidence of fetal infection or that were achieved by assisted reproduction technologies were excluded from the study. IUGR was defined as an estimated fetal weight and (later) confirmed birthweight of <10th percentile according to local reference curves. In total, 132 IUGR fetuses were included for the study in prenatal life; 4 fetuses were later excluded because of Down’s syndrome (2 fetuses) and pulmonary stenosis (2 fetuses); 5 fetuses died before delivery, and 11 fetuses died in the neonatal period. From the remaining 112 patients, 12 were lost on follow up, which left us with 100 IUGR cases. The reference cohort of fetuses with normal estimated fetal weight and birthweight ( 10th-90th percentile ) were sampled randomly from pregnancies at our institution and paired with IUGR cases by gestational age at scan (±1 week). The study was approved by our institution’s Ethics Committee, and written parental consent was obtained for all study participants. The study protocol included fetal standard obstetric assessment and echocardiography, record of delivery data, and postnatal vascular assessment at 6 months of corrected age.
Baseline and perinatal characteristics
At fetal examination, maternal characteristics such as height, weight, body mass index, smoking during pregnancy, and parity were recorded. Gestational age at scan was calculated based on the crown-rump length that had been obtained at the first-trimester screening. All women underwent ultrasonographic examination with a Siemens Sonoline Antares machine (Siemens Medical Systems, Malvern, PA) that included estimation of fetal weight and standard obstetric Doppler evaluation that comprised measurement of the pulsatility index (PI) for the uterine arteries, umbilical artery, middle cerebral artery, ductus venosus, and aortic isthmus. Both estimated fetal weight and birthweight percentile were calculated with local reference curves. Uterine artery evaluation was performed with the probe placed on the lower quadrant of the abdomen, angled medially, with identification by color Doppler imaging of the apparent crossover with the external iliac artery. Mean uterine artery PI was calculated as the average PI of right and left arteries. Umbilical artery was evaluated in a free loop of the umbilical cord; middle cerebral artery was measured in a transverse view of the fetal skull at the level of its origin from the circle of Willis. Cerebroplacental ratio was calculated by division of middle cerebral artery and umbilical artery PI. Ductus venosus was obtained from a mid-sagittal or alternatively a transverse section of the fetal abdomen before its entrance into the inferior vena cava, with the Doppler gate positioned at the isthmic portion. The aortic isthmus was obtained either in a sagittal view of the fetal thorax with a clear visualization of the aortic arch by placement of the Doppler sample volume between the origin of the left subclavian artery and the confluence of the ductus arteriosus or in a cross section of the fetal thorax at the level of the 3-vessel and trachea view, with the Doppler gate placed in the aorta just before the convergence of the arterial duct. On delivery, gestational age, birthweight, birthweight percentile, mode of delivery, Apgar scores, presence of preeclampsia, and length of stay at the neonatal intensive care unit were recorded.
Fetal echocardiography
On IUGR diagnosis, a complete 2-dimensional echocardiographic examination was performed initially to assess structural heart integrity with a Siemens Sonoline Antares machine (Siemens Medical Systems). Cardiovascular evaluation was performed with a curved-array 2-6 MHz transducer (with the exception of tissue Doppler measurements that required a phased-array 2-10 MHz transducer). The following measurements were performed:
Cardiac morphometry included cardiothoracic ratio, atrial areas, ventricular sphericity indexes, and myocardial wall thicknesses. The cardiothoracic ratio was measured from a 4-chamber view, by the area method previously described. Left and right atrial areas were delineated on 2-dimensional images from an apical or basal 4-chamber view at end-ventricular systole (maximum point of atrial distension). Ventricular base-to-apex lengths and transverse diameters were measured on 2-dimentional images from an apical 4-chamber view at end-diastole. Ventricular sphericity indexes were calculated as base-to-apex length/transverse diameter of the left and right ventricles, respectively. Ventricular end-diastolic septal and free wall thicknesses were measured by M-mode from a transverse 4-chamber view.
Systolic function evaluation included ejection fraction (EF), stroke volume (SV), cardiac output (CO), cardiac index, mitral/tricuspid annular-plane systolic excursion (MAPSE/TAPSE), systolic annular peak velocity (S’), and the isovolumic contraction (IVCT) and ejection time (ET). Left and right EFs were obtained from a transverse 4-chamber view by M-mode, with Teicholz’s formula. Left and right SVs were calculated as
π 4 × ( aortic or pulmonary valve diameter ) 2 × ( aortic or pulmonary artery systolic flow velocity – time integral ) .
Fetal heart rate was calculated in the spectral Doppler image of the aortic or pulmonary flow. Aortic systolic flow was obtained in an apical or basal 5-chamber view of the heart, and the pulmonary artery systolic flow was obtained in a right ventricle outflow tract view; both were at angles as close to 0 degrees as possible. Velocity-time integrals were calculated by manual trace of the spectral Doppler area. Left and right COs were calculated as left/right SV × fetal heart rate. Diameters of the aortic and pulmonary valves were measured in frozen real-time images during systole by the leading edge-to-edge method. Cardiac index was obtained by the formula
and expressed in milliliters per minute per kilogram. MAPSE and TAPSE that were assessed by M-mode were measured real time in an apical or basal 4-chamber view by placement of the cursor at a right angle to the atrioventricular junction and marked by the valve rings at the mitral or tricuspid valves ; maximum amplitude of motion was taken as the extent of displacement between end-systole and end-diastole, measured in millimeters. Tissue Doppler imaging was applied in spectral Doppler mode at mitral and tricuspid lateral annuli from an apical or basal 4-chamber view, to record S’ in centimeters per second. The IVCT and ET were obtained in a cross section of the fetal thorax at the 4-chamber view, which placed the Doppler sample volume on the medial wall of the ascending aorta and included the aortic and mitral valve; valvular clicks in the Doppler wave were used as landmarks to calculate each. The IVCT was measured from the closure of the mitral valve to the opening of the aortic valve, and the ET was measured from opening to closure of the aortic valve.
Diastolic function was evaluated by peak early/late transvalvular filling velocities ratio, early diastolic (E) velocity deceleration time, early diastolic annular peak velocity (E’), E/E’ ratio, and left isovolumic relaxation time (IVRT). Atrioventricular flow velocities were obtained from a basal or apical 4-chamber view, which placed the pulsed Doppler sample volume just below the valve leaflets. E deceleration time was measured as the time from the maximum mitral/tricuspid velocity to the baseline. Tissue Doppler imaging was applied in spectral Doppler mode at the mitral and tricuspid lateral annuli, from an apical or basal 4-chamber view to record E’ in centimeters per second. Left IVRT was measured in the same plane as IVCT and ET from the closure of the aortic valve to the opening of the mitral valve.
Anthropometric and vascular assessment at 6 months of corrected age
We calculated the estimated date of delivery based on the first-trimester crown-rump length (ie, 40 weeks’ gestation) and scheduled follow-up evaluation 6 months from this date (6 months of corrected age). Postnatal assessment included anthropometric data, blood pressure, and vascular ultrasound assessment.
Anthropometric data included the infant’s height, weight, body mass index, and body surface area that were measured at the time of the examination.
Systolic and diastolic blood pressures from the brachial artery were obtained by a trained physician at the beginning of the medical evaluation who used a validated ambulatory automated device (Omron 5 Series; Omron Corporation, Kyoto, Japan), while the infant was resting.
Vascular assessment by ultrasound scan was performed with Vivid Q (General Electric Healthcare, Horten, Norway), with a 12L-RS linear-array 6.0-13.0 MHz transducer. Infants were studied when resting quietly or asleep. Longitudinal clips of the far wall of the proximal abdominal aorta in the upper abdomen were obtained, and aIMT measurements were performed offline according to a standardized protocol based on a trace method with the assistance of commercially available software (GE EchoPAC PC 108.1.x; General Electric Healthcare). To obtain aIMT measurements, 3 end-diastolic frames were selected across a length of 10 mm and analyzed for mean and maximum aIMT; the average reading from these 3 frames was calculated.
Cardiovascular endpoint: hypertension and arterial remodeling
To define hypertension and arterial remodeling, we sought those parameters that have been reported in the literature as sensitive for the detection of preclinical cardiovascular dysfunction in infants. Thus, the cardiovascular endpoint of hypertension and arterial remodeling at 6 months of age was defined as the presence of both a mean blood pressure of >95th percentile and maximum aIMT of >75th percentile. Blood pressure percentiles were calculated according to published reference values. Because no reference values exist for aIMT at this age, we used percentiles that had been obtained with our control group as reference parameters.
Statistical analysis
Data were analyzed with the use of the IBM SPSS Statistics 19 (IBM Corporation, Armonk, NY) and MedCalc statistical software (version 9.1; MedCalc Software, Ostend, Belgium). Sample size was calculated to enable us to observe a difference of 10% in fetal TAPSE values for IUGR as compared with control subjects. Fetal TAPSE was chosen because of its high sensitivity for preclinical cardiac dysfunction in fetuses and children. For a power of 80% and alpha risk of 0.05, a minimum of 97 subjects per study group was required.
First, a comparative study between control and IUGR fetuses and infants was performed. Normality was evaluated by the Shapiro-Wilk test. Baseline and perinatal characteristics were compared in cases and control subjects with the Student t test. Comparison of fetal echocardiographic parameters was performed by linear regression and adjusted by gender, gestational age at delivery, preeclampsia in fetuses, and body surface area in infants. Probability values < .05 were considered statistically significant.
Second, the association and predictive value of standard perinatal data and fetal echocardiography for infant hypertension and arterial remodeling were assessed within the IUGR group. Infant hypertension and arterial remodeling at 6 months of age were defined as mean blood pressure of >95th percentile along with aIMT of >75th percentile. Data were analyzed by logistic regression to obtain odds ratios (ORs) for the cardiovascular parameters that were associated with the infant vascular outcome. To account for changes because of gestational age, fetal parameters were included as z-scores (when available) in the model. Finally, a composite score that was based on the strongest predictors was generated by multivariate logistic regression, and receiver operating characteristic curve analysis was used for the calculation of the area under the curve for the score and standard perinatal parameters.
Results
Baseline perinatal and delivery characteristics
Baseline characteristics of the pregnant group are shown in Table 1 . All patients’ prenatal and postnatal diagnoses were concordant. Maternal characteristics were similar in IUGR cases and control subjects. Mean gestational age at scan was 35.3 weeks of gestation for control subjects (range, 28.2–40.0 weeks’ gestation) vs 35.8 weeks’ gestation (range, 26.3–40.0 weeks’ gestation; P = .424) in the IUGR group. As expected, estimated fetal weight and fetoplacental Doppler parameters were significantly worse in the IUGR group. The growth-restricted group showed an earlier gestational age at delivery, with lower birth weight percentile and worse perinatal outcomes, which was shown by a higher incidence of preeclampsia, prematurity, cesarean delivery, and longer neonatal hospitalization.
| Variables | Control subjects (n = 100) | Intrauterine growth restriction (n = 100) | P value a |
|---|---|---|---|
| Maternal characteristics | |||
| Height, cm b | 162 ± 7 | 161 ± 6 | .279 |
| Weight, kg b | 61 ± 11 | 59 ± 13 | .242 |
| Body mass index, kg/m 2 b | 22 ± 4 | 23 ± 5 | .120 |
| Smoking, % | 21 | 24 | .735 |
| Nulliparity, % | 57 | 67 | .190 |
| Fetoplacental ultrasound evaluation b | |||
| Gestational age at ultrasound, wk | 35.3 ± 5.1 | 35.8 ± 3.6 | .424 |
| Estimated fetal weight, g | 2270 ± 889 | 1960 ± 626 | .005 |
| Estimated fetal weight percentile | 52 ± 24 | 2 ± 3 | < .001 |
| Mean uterine artery pulsatility index | 0.68 ± 0.18 | 0.88 ± 0.43 | .001 |
| Umbilical artery pulsatility index | 1.03 ± 0.21 | 1.25 ± 0.58 | .002 |
| Middle cerebral artery pulsatility index | 2.01 ± 0.35 | 1.56 ± 0.48 | < .001 |
| Cerebroplacental ratio | 2.02 ± 0.53 | 1.46 ± 0.73 | < .001 |
| Ductus venosus pulsatility index I | 0.52 ± 0.16 | 0.55 ± 0.19 | .229 |
| Aortic isthmus pulsatility index | 2.67 ± 0.36 | 3.92 ± 2.87 | < .001 |
| Pregnancy outcomes | |||
| Gestational age at delivery, wk b | 40.1 ± 1.5 | 37.2 ± 3.5 | < .001 |
| Delivery <37 wk gestation, % | 0 | 20 | < .001 |
| Birthweight, g b | 3373 ± 412 | 2153 ± 664 | < .001 |
| Birthweight percentile b | 50 ± 25 | 3 ± 3 | < .001 |
| Cesarean delivery, % | 16 | 42 | < .001 |
| 5-minute Apgar score <7, % | 0 | 1 | 1.000 |
| Preeclampsia, % | 1 | 10 | .013 |
| Neonatal intensive care unit, d b | 1 ± 4 | 11 ± 22 | < .001 |
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