Gestational Age In Normal Fetuses Research Articles

Area of the Fetal Ascending and Descending Aorta by Spatiotemporal Image Correlation in the Rendering Mode: Reproducibility and Comparison with Pregestational Diabetic Mothers.

The objective of this study was to assess the ascending and descending aorta area measurements by three-dimensional (3D) ultrasound using spatiotemporal image correlation (STIC) in the rendering mode comparing these measurements with pregestational diabetic mothers and assessing the reproducibility of the method. We carried out a retrospective cross-sectional study with 58 normal and nine fetuses from pregestational diabetic mothers between 20 and 33 + 6 weeks of gestation. Fetal heart volumes were acquired at the level of four-chamber view to obtain the reconstructed planes for the ascending and descending aorta areas in the rendering mode. Linear regression was performed to assess the correlation between the fetal aorta areas and gestational age (GA). To assess the intra- and interobserver reproducibility, we used the concordance correlation coefficient (CCC). The mean ascending and descending aorta areas were 0.12 (0.02-0.48) and 0.11 (0.04-0.39) cm2 in normal fetuses, respectively. There was a moderate positive correlation between GA and ascending aorta area measurements (0.005676*GA - 0.01283; r = 0.53, P < 0.0001) and strong positive correlation between GA and descending aorta area (0.01095*GA - 0.1581; r = 0.68, P < 0.0001). We observed a weak intra- and interobserver reproducibility with CCC ranging from 0.05 to 0.91. The mean difference in the ascending and descending aorta area measurements of normal and fetuses of pregestational diabetic mothers was -0.03 cm2 (P = 0.276) and -0.03 cm2 (P = 0.231), respectively. The fetal ascending and descending aorta area measurements obtained by 3D ultrasound using STIC in the rendering mode increased with GA in normal fetuses. The method showed weak intra- and interobserver reproducibility.

Perinatal changes of right ventricle-pulmonary artery coupling and its value in predicting persistent pulmonary hypertension of the newborn.

Right ventricle-pulmonary artery (RV-PA) coupling is an independent predictor of outcome in pulmonary arterial hypertensionin adults. Here, we aimed to investigate the changes in RV-PA coupling during the perinatal period, and to evaluate its performance on predicting persistent pulmonary hypertension of the newborn (PPHN). A total of 1196 fetuses underwent a dedicated echocardiography screening for foetal heart defects during second trimester (24-27 weeks' gestation), third trimester (34-37 weeks' gestation) and neonatal period (within 14 days after delivery) with the measurement of tricuspid annular plane systolic excursion (TAPSE) and mean pulmonary artery pressure (MPAP). The RV-PA coupling (TAPSE/MPAP ratio) was calculated. Six fetuses were diagnosed as persistent pulmonary hypertension of the newborn(PPHN). In normal fetuses, RV-PA coupling had been increasing from the second trimester to the third trimester and then to the neonatal period (0.12 ± 0.02 vs. 0.18 ± 0.05 vs. 0.23 ± 0.08 mm/mmHg, p < 0.05), while it had been decreasing during the same period of time in abnormal fetuses (0.18 ± 0.02 vs. 0.17 ± 0.02 vs. 0.17 ± 0.01 mm/mmHg, p < 0.05). There was a strong positive correlation between RV-PA coupling and gestational age (GA) in normal fetuses (r = 0.71, p < 0.0001). The area under receiver operating characteristic curve (AUC) of 0.989 for RV-PA coupling during second trimester was superior to that for RV-PA coupling during third trimester (AUC: 0.536) in predicting PPHN. The optimal cutoff value was 0.16 mm/mmHg, with a sensitivity of 100.00%, a specificity of 96.36%and an accuracy of 97.73%. RV-PA coupling had close relation with GA in normal fetuses. It was a strong predictor of PPHN.

Improved differentiation between hypo/hypertelorism and normal fetuses based on MRI using automatic ocular biometric measurements, ocular ratios, and machine learning multi-parametric classification.

To differentiate hypo-/hypertelorism (abnormal) from normal fetuses using automatic biometric measurements and machine learning (ML) classification based on MRI. MRI data of normal (n = 244) and abnormal (n = 52) fetuses of 22-40 weeks' gestational age (GA), scanned between March 2008 and June 2020 on 1.5/3T systems with various T2-weighted sequences and image resolutions, were included. A fully automatic method including deep learning and geometric algorithms was developed to measure the binocular (BOD), inter-ocular (IOD), ocular (OD) diameters, and ocular volume (OV). Two new parameters, BOD-ratio and IOD-ratio, were defined as the ratio between BOD/IOD relative to the sum of both globes' OD, respectively. Eight ML classifiers were evaluated to detect abnormalities using measured and computed parameters. The automatic method yielded a mean difference of BOD = 0.70 mm, IOD = 0.81 mm, OD = 1.00 mm, and a 3D-Dice score of OV = 93.7%. In normal fetuses, all four measurements increased with GA. Constant values were detected for BOD-ratio = 1.56 ± 0.05 and IOD-ratio = 0.60 ± 0.05 across all GA and when calculated from previously published reference data of both MRI and ultrasound. A random forest classifier yielded the best results on an independent test set (n = 58): AUC-ROC = 0.941 and F1-Score = 0.711 in comparison to AUC-ROC = 0.650 and F1-Score = 0.385 achieved based on the accepted criteria that define hypo/hypertelorism based on IOD (< 5th or > 95th percentiles). Using the explainable ML method, the two computed ratios were found as the most contributing parameters. The developed fully automatic method demonstrates high performance on varied clinical imaging data. The new BOD and IOD ratios and ML multi-parametric classifier are suggested to improve the differentiation of hypo-/hypertelorism from normal fetuses. • A fully automatic method for computing fetal ocular biometry from MRI is proposed, achieving high performance, comparable to that of an expert fetal neuro-radiologist. • Two new parameters, IOD-ratio and BOD-ratio, are proposed for routine clinical use in ultrasound and MRI. These two ratios are constant across gestational age in normal fetuses, consistent across studies, and differentiate between fetuses with and without hypo/hypertelorism. • Multi-parametric machine learning classification based on automatic measurements and the two new ratios improves the identification of fetal ocular anomalies beyond the accepted criteria (<5th or >95th IOD percentiles).

Fetal Transverse Cerebellar Diameter (TCD) Measurement for Gestational Age Prediction in the Second and Third Trimesters of Pregnancy

Background: The purpose of this study was to see how accurate transverse cerebellar diameter (TCD) measurement is at predicting gestational age in normal fetuses. In the 2 nd &amp; 3 rd trimesters of pregnancy a range of sonographics fetal biometric characteristics can be utilized to determine gestational age. Other parameters, such as bi-parietal diameter and fetal length, are used to determine transcerebellar diameter. Objective(s): To determine the predictability of GA estimated from fetal TCD assessed on ultrasonography in the 2 nd and 3 rd trimesters of pregnancy. Methodology: This was a cross-sectional study conducted at the Ch. Mohammad Akram teaching and research hospital on 84 pregnant healthy ladies with fetuses ranging in age from 18 to 45 years old. During the 2 nd and 3 rd trimesters of pregnancy a routine ultrasound scan was done. In additions to the standard biometric parameter the transcerebellar diameter was estimated. Results: The TCD of 84 patients as a measure of gestational age in weeks. These were generated from data collected during the study and include mean and standard deviation TCD measurements of 84 participants ranging in gestational age from 14 to 40 weeks. The current research found a significant link between the GA of TCD and the GA of BPD and fetal length. The TCD(mm) mean and standard deviations were 33.74 ± 11.762 respectively. The TCD gestational age mean and standard deviations were 28.160 ± 6.7942 respectively. Bi-parietal diameter (mm) has a mean and standard deviation of 68.24 ± 18.503. Bi-parietal diameter had a mean and standard deviation of 27.996 ± 6.9099 gestational age. The standard deviation and mean 50.32 ± 16.265 mm Fetal length The mean and standard deviation of fetal length gestational age are 27.423 ± 6.7625. Different criteria such as transcerebellar diameter, biparietal diameter, and femur length, are used to establish the gestational age of the fetus in this cross-sectional analysis. Conclusion(s): The TCD is a set of accurate variables for assessing GA in pregnant women in the 2 nd and 3 rd trimesters. Key words: Transcerebellar diameter; Gestational age; Fetal length ; Bi-parietal diameter. DOI: 10.7176/JHMN/93-08 Publication date: September 30 th 2021

Measurement of the Brain Volume/Liver Volume Ratio by Three-Dimensional MRI in Appropriate-for-Gestational Age Fetuses and Those With Fetal Growth Restriction.

Fetal growth restriction (FGR) is associated with a high fetal brain volume/liver volume (FBV/FLV) ratio. Ultrasound may not always be reliable, which has prompted further investigation of MRI techniques. To determine the relationship between FBV/FLV ratio, as measured by MRI, and gestational age (GA) in normal fetuses and those with FGR. Retrospective. One hundred and forty seven singleton pregnancies including 105 appropriate-for-gestational age (AGA) fetuses and 42 FGR fetuses. Three-dimensional fast imaging employing steady-state acquisition at 1.5 T. The FBV and FLV were measured by three radiologists. The inter- and intraobserver agreements, the correlation between FBV/FLV ratio, and advancing GA were evaluated; the diagnostic value of FBV/FLV ratio was evaluated and compared with head circumference/abdominal circumference (HC/AC) ratio measured by ultrasound. Intraclass correlation coefficient (ICC) was used to determine inter- and intraobserver agreements. Regression analysis was used to assess the correlation between FBV/FLV ratio and advancing GA. The diagnostic value of the FBV/FLV ratio was examined by the area under the receiver operating characteristic (ROC) curve. The inter- and intraobserver agreements were excellent with an interobserver ICC of 0.984 and intra-observer ICCs of 0.989, 0.994, and 0.995. The FBV/FLV ratio in AGA fetuses decreased significantly with advancing GA (Pearson correlation coefficient=-0.844). The FBV/FLV ratio in FGR fetuses was significantly higher than that in AGA fetuses. To identify fetuses at high risk for FGR using the FBV/FLV ratio, the area under the ROC curve was 0.978, with an optimal cut-off value of 4.10. The sensitivity of FBV/FLV ratio in identifying FGR was significantly higher than that of HC/AC ratio (0.929 vs. 0.529). An inverse correlation exists between FBV/FLV ratio and advancing GA in normal fetuses. A high FBV/FLV ratio may be used to ascertain fetuses at high risk for FGR. 3 Technical Efficacy Stage: 3.

Ultrasound measurement of fetal arterial pulse pressure using phased-tracking methods: A phantom study and clinical experience with antenatal corticosteroid therapy.

This study aimed to compare the accuracy of fetal pulse pressure estimated with a vascular simulator with that obtained by a manometer (reference) and evaluate the pulse pressure in normal human fetuses and fetuses whose mothers received corticosteroids. Fetal pulse pressure was estimated as the product of blood flow velocity and pulse wave velocity, based on the water hammer equation. Ultrasonic raw radiofrequency signals for blood flow velocity were captured from the fetal descending aortas at the diaphragm level, and pulse wave velocity was simultaneously measured from different directions using the phased-tracking method. First, the precision and accuracy of pulse pressure in the estimated method were verified by a circulatory phantom simulator, which reproduced fetal blood flow using a pulsating pump. Then, the pulse pressure of 98 normal human fetuses after 17 weeks of gestation and the fetal pulse pressure in 21 mothers who received antenatal corticosteroids for fetal maturation were measured. A significant correlation between the estimated pulse pressure values and the actual values was found in the phantom simulation (r = 0.99, P < 0.01). The estimated pulse pressure was significantly correlated with gestational age in normal fetuses (r = 0.74, P < 0.01). In steroid-treated pregnant women, fetal pulse pressure was observed to increase significantly on the second day of administration (P < 0.01). A noninvasive and accurate estimation model of fetal pulse pressure could be established using phased-tracking method, and this method has the potential to improve the assessment of human fetal hemodynamics.

A Nomogram of Lateral Abdominal Wall Fat Thickness in Normal Third Trimester Fetuses

The objective of this study is to establish a nomogram of fetal abdominal wall fat thickness in fetuses with known normal neonatal outcomes. After IRB approval (HSD-49496), 157 ultrasound examinations in 100 patients, 41 of whom had multiple examinations during the same pregnancy were reviewed. The thickness of the fetal lateral abdominal wall fat Interreader agreement was summarized using the intraclass correlation coefficient (ICC). Fat thickness growth curve equations were estimated to quantify the relationship between fat thickness and gestational age. The abdominal wall fat had an intraclass correlation coefficient of 0.93 (95% confidence interval, 0.90-0.96) for 2 readers. Fat thickness increased in all 41 fetuses with multiple examinations (P < 0.001). Fat thickness increased 0.19 mm per week on average (95% confidence interval, 0.17-0.21 mm; P < 0.001) from an average of 1.7 mm at 22 weeks and 4.3 mm at 36 weeks. Lateral wall abdominal fat can be reproducibly measured with good inter observer correlation, and fat does increase with increasing gestational age in normal fetuses. We believe the utility of fetal fat is the documentation of its presence as a reassuring finding indicative of normal fetal health, particularly when prior dating is discrepant or not available during the third trimester.

Developmental Changes in Aortic Mechanical Properties in Normal Fetuses and Fetuses with Cardiovascular Disease

We hypothesized that fetal aortic mechanical properties assessed by aortic diameter (AoD) and flow show maturational changes during the gestational period, and that these properties are different in fetuses with congenital heart diseases and fetuses with normal development. Phasic changes in ascending AoD along with Doppler flow profile were measured in 84 consecutive normal fetuses (gestational age, 18-36weeks) and in 30 consecutive fetuses with cardiovascular diseases (gestational age, 22-39weeks). AoD and cardiac output significantly increased with gestational age. Fetal aortic compliance (AC), assessed as (maximum AoD - minimum AoD)/stroke volume, significantly decreased with gestational age in normal fetuses, indicating maturational changes in aortic wall properties. Importantly, fetuses with Marfan syndrome and tetralogy of Fallot that exhibit "aortopathy" showed significantly lower AC than normal fetuses of the same gestational age, suggesting intrinsic abnormalities in aortic wall properties in these diseases. Fetuses with trisomy 18 and Noonan syndrome also had AC values below the normal ranges. Measurements of phasic changes in fetal AoD and flow measurements can provide useful information about aortic mechanical properties and may help clarify abnormal arterial hemodynamics in pathologic conditions.

Predictive role of prenasal thickness and nasal bone for Down syndrome in the second trimester

ObjectiveTo assess the efficacy of prenasal thickness (PNT) and nasal bone (NB) for prediction of Down syndrome (DS) fetuses in the second trimester ultrasound examination. Study designPNT was measured from stored two-dimensional fetal profile images taken at 15–23 weeks in 242 fetuses with normal karyotype (Group 1) and 24 fetuses with DS (Group 2). It was measured as the shortest distance from the anterior edge of the lowest part of the frontal bone to the skin. The efficacy of PNT, NB, PNT/NB and biparietal diameter (BPD)/NB was evaluated for prediction of DS. ResultsPNT values increased with gestational age in normal fetuses. PNT measurement was ≥95th percentile in 54.2% (13/24) of the DS cases and 2.9% of the normal cases. Receiver operator curve analysis showed that PNT/NB ratio had the best area under the curve with a detection rate of 80% for a false positive rate of 5% at a cut-off value of 0.76. ConclusionsPNT is increased in fetuses with DS as compared to normal fetuses. PNT/NB ≥0.76 in the second trimester is a better predictor of DS than the use of PNT or NB alone.

Cisterna magna width at 11–13 weeks in the detection of posterior fossa anomalies

To construct reference ranges for cisterna magna (CM) width at 11-13 weeks' gestation in healthy fetuses and determine whether open spina bifida and posterior fossa anomalies could be diagnosed in the first trimester. This was a retrospective study. CM width reference ranges were constructed based on the measurements obtained from 80 healthy fetuses with normal postnatal outcome undergoing routine first-trimester ultrasound at 11-13 weeks, using the Lambda-Mu-Sigma method. CM was measured in the fetal mid-sagittal view, as routinely used for nuchal translucency assessment. In addition, first-trimester ultrasound images in 11 fetuses with open spina bifida or posterior fossa anomalies, most of which were diagnosed later in pregnancy, were retrospectively reviewed, and CM measurements were compared against reference ranges. CM width was noted to increase with gestational age in normal fetuses. The anomalies in the 11 fetuses we reviewed were: open spina bifida (n = 5), megacisterna magna (n = 3), Blake's pouch cyst (n = 2) and posterior fossa arachnoid cyst (n = 1). All fetuses with open spina bifida had a CM width below the 5(th) percentile. In the two fetuses with Blake's pouch cyst and in two with megacisterna magna, CM width was above the 95(th) percentile. In one of the fetuses with a megacisterna magna and the one with an arachnoid cyst, CM width was within normal range. We have constructed reference ranges for CM width at 11-13 weeks using the mid-sagittal view. It appears that first-trimester CM width can be used as a marker for the early detection of open spina bifida. However, our findings need to be confirmed in prospective large series.

Quantitative MRI measurements of human fetal brain development in utero

Magnetic resonance imaging (MRI) allows for high resolution imaging of the central nervous system. We have tested the feasibility of using MRI in conjunction with quantitative image analysis to perform volumetric measurements of the brain in the developing human fetus in utero. The database comprises MR images of a total of 56 fetuses (gestational age 25–41 weeks) referred because of suspected abnormalities due to ultrasound findings, family history or maternal illness and scanned on a 1.5 T MR system using a single-shot fast spin echo (SSFSE) T2 sequence, slice thickness 3 mm, no gap. Four out of the 56 scans could not be used in the analysis due to poor image quality. Automatic segmentation (using NIH Image routines) was found to be unreliable in these fetal brains, so cerebral, cerebellar and ventricular regions were traced manually. Ventricular volumes did not vary with gestational age in normal fetuses ( N = 27, R = 0.05, p = 0.8) while cerebral parenchyma and cerebellum volumes increased significantly during the same period ( R = 0.67, p = 0.0002 and R = 0.51, p = 0.0066 respectively). Two calculated parameters: percent ventricular asymmetry and volume ratio of ventricles to hemispheric parenchyma were found to be very sensitive to ventricular pathology; such that the mean value of the latter in normal fetuses was 4.4% ± 0.56 (mean ± SEM, N = 27) compared to 34.3% ± 17.6 ( N = 6, p < 0.0001) in fetuses with ventriculomegaly. These results support the use of image analysis and MRI to produce normal growth curves as well as quantitative severity assessments of brain pathologies in the developing human fetus.

Fetal ear length measurement: a useful predictor of aneuploidy?

To determine the usefulness of short ear length (EL) measurement in the prenatal detection of fetuses with chromosomal abnormalities. Fetal EL measurements, routine biometry and complete anatomic survey for fetal abnormalities were prospectively performed by antenatal sonography. One thousand eight hundred and forty-eight patients with singleton pregnancies undergoing genetic amniocentesis in the second or third trimester. Complete data for EL, biometry and anatomic survey for major structural abnormalities and minor sonographic markers of chromosomal abnormality were available in 1311 fetuses. Of these, 48 (3.7%) had an abnormal karyotype and 1263 (96.3%) had a normal karyotype. Using an EL measurement of < or = 10th percentile for corresponding gestational age in normal fetuses as abnormal cut-off values, detection rates for chromosomal abnormalities by short EL were determined. Among the 48 abnormal karyotypes, 34 were considered significant, and 11 of these 34 (32.4%) fetuses had short EL. In 14 cases, the karyotypic abnormality was considered non-significant and fetal EL was normal in all cases. Of the 34 fetuses with significant chromosomal abnormalities, six (17.6%) on antenatal sonography had no detectable abnormal findings, other than short EL. An increased biparietal diameter (BPD)/EL ratio of > or = 4.0 was also noted in fetuses with an abnormal karyotype, but the sensitivity and predictive value of increased BPD/EL ratio alone or increased BPD/EL ratio in combination with short EL was no better than the sensitivity and predictive value of short EL alone. A combination of short EL and abnormal ultrasound, however, gave a much higher positive predictive value (46%) for significant chromosomal abnormalities. Our findings suggest that in women at high risk for fetal chromosomal abnormality, a short fetal EL measurement on prenatal ultrasound, either alone or in combination with other sonographically detectable structural abnormalities, may be a useful parameter in predicting fetal aneuploidy.

Transvaginal sonographic measurement of fetal lingual width in early pregnancy

Our objective was to construct a nomogram of the fetal lingual size early pregnancy and to assess the size of the tongue in abnormal fetuses. The lingual width was measured by using transvaginal ultrasonography in 80 normal fetuses at 13 and 18 weeks' gestation. In addition the tongue was measured in 22 fetuses at these gestational ages who had an abnormal karyotype or oro-facial malformations. A linear relationship was found between the lingual width and gestational age in normal fetuses. The lingual size was within the normal range in cases of trisomy 13, trisomy 21 and Turner syndrome. A small tongue was observed in fetuses with micrognathia. Correlation between lingual width and gestational age was observed in early pregnancy. The relationship between the size of the tongue and oro-facial malformation needs further evaluation.

Atrial natriuretic factor, digoxin-like immunoreactive substance, norepinephrine, epinephrine, and plasma renin activity in human fetuses and their alteration by fetal disease

We measured five hormones presumably involved in fetal homeostasis in specimens obtained by cordocentesis for clinical indications from 106 fetuses. Norms for atrial natriuretic factor, digoxin-like immunoreactive substance, plasma renin activity, norepinephrine, and epinephrine were derived from fetuses ultimately shown to be free of detectable abnormality. Atrial natriuretic factor, digoxin-like immunoreactive substance, and plasma renin activity were unrelated to umbilical vessel source or gestational age. Digoxin-like immunoreactive substance was directly related to Pco2 (r = 0.63, p = 0.02). Digoxin-like immunoreactive substance level was elevated in all fetal disease states studied except isoimmunization. The level of atrial natriuretic factor was elevated in fetuses with immune hydrops (NS). Norepinephrine and epinephrine levels were higher in the umbilical artery than in the vein (p = 0.05 and 0.006, respectively). There was a significant correlation between norepinephrine and gestational age in normal fetuses (r = 0.7637, p < 0.025) and between both catecholamines and many of the respiratory blood gas measurements, with pH and Pco2 being the major determinants. Most disease states were associated with an elevated norepinephrine concentration. There was a negative correlation between plasma renin activity and base deficit (p < 0.0001). Plasma renin activity was elevated in fetuses with idiopathic growth retardation and nonimmune hydrops (p < 0.05 for each). In summary, fetal homeostasis as reflected by these five hormones was altered by a variety of disorders. With these baseline values the effects of direct or indirect fetal therapy can begin to be studied.

Fetal head and abdominal circumferences: II. A critical re-evaluation of the relationship to menstrual age.

Dynamic image ultrasound was utilized to re-examine the changes in head and abdominal circumferences (HC, AC) with gestational age in normal fetuses. Data collected in a cross-sectional study of fetal growth were evaluated using mathematical modeling techniques. The results of this analysis indicated that a linear-cubic function optimally fits the HC data (R2 = 97.3%) while the AC data was fitted optimally by a linear function (R2 = 95.5%). The predicted values calculated from these functions were in very close agreement [mean deviation (absolute value): 1.97% (HC), 1.38% (AC)] with those calculated from average functions for HC and AC obtained in a previous longitudinal growth study. Variability was not constant throughout pregnancy for either HC or AC. With HC the normal range changed from +/-1.5 cm to +/-2.5 cm at 28 wk (menstrual age). The AC variability increased progressively with increasing menstrual age and was shown to be related to the predicted AC value. The normal range was found to be 13% of the predicted AC value throughout pregnancy. Based on these results, a new set of normal HC and AC values for the 12-40 wk (menstrual age) period is presented.

Increased heart rate response to parasympathetic and beta adrenergic blockade in growth-retarded fetal lambs

To determine the influence of the autonomic nervous system on the circulation of normal and growth-retarded fetal lambs we measured the responses of heart rate and arterial blood pressure to parasympathetic (atropine 0.2 mg/kg) and β-adrenergic (propranolol 1.0 mg/kg) blockade in the last quarter of gestation. The heart rate response to parasympathetic blockade increased with gestational age in both normal and growth-retarded fetuses but in the growth-retarded fetuses there was a significantly greater response to parasympathetic blockade than in control fetuses from 121 days' gestation to term. The heart rate response to β-adrenergic blockade did not change with gestational age in normal fetuses. From 131 days' gestation to term the heart rate response to β-adrenergic blockade in growth-retarded fetuses was significantly higher than in normal fetuses. The systemic arterial blood pressure responses to parasympathetic or β-adrenergic blockade were similar in growth-retarded and normal fetuses. These results indicate an increased parasympathetic and β-adrenergic influence on the heart of fetuses whose growth has been retarded. It may also suggest a more generalized increase in parasympathetic and sympathetic tone affecting other organs and systems in the growth-retarded fetal lambs.