Fetal Soft Tissue Research Articles

What is the value of ultrasound soft tissue measurements in the prediction of abnormal fetal growth?

SummaryAbnormal fetal growth increases the complications of pregnancy not only for the baby but also for the mother. Growth abnormalities also have lifelong consequences. These babies are at increased risk of insulin resistance, diabetes and hypertension later in life. It is important to identify these babies antenatally to optimise their clinical care. Although used extensively antenatally to monitor fetal growth, ultrasound has its limitations. Despite the use of more than 50 different formulae to estimate fetal weight, their performance has been poor at the extremes of fetal weight. Over the past 20 years there has been emerging interest in studying fetal soft tissue measurements to improve detection of growth abnormalities. This review paper outlines the value of soft tissue measurements in identifying fetal growth abnormalities, in estimating fetal weight and in managing diabetes mellitus in pregnancy.

OC038: Sonographic assessment of the normal fetal secondary palate using a novel three‐dimensional ultrasound approach

The aim of this study is to describe a three-dimensional (3D) ultrasound rendering technique to examine the normal fetal secondary palate and to assess its correlation to the real fetal anatomy. A prospective study was leaded and included 122 fetuses in a low risk population. Fetal ultrasound examinations were performed at 17, 22, 27 and 32 weeks' gestation to determine the normal 3D view of the fetal palate at different gestational ages. The ultrasound scan was performed using strict anterior axial plane of starting reconstruction volume. 3D underside view was obtained. The visualization rates of seven defined anatomical landmarks of the palate are computed for each gestational age. The 3D-view of the fetal secondary palate was compared to the normal anatomic view obtained by surgical foetopathologist examination of fetuses. The visualization rates across gestational ages are compared by use of the Cochrane Q test. The reliability of detection of each anatomical landmark across gestational ages is determined by Cronbach's Alpha. To examine the fetal soft tissues, ultrasound scans were studied at 22 weeks of gestation. The sonographer used an 30°-inclinated axial 3D-view of the fetal palate. The visualization rates of the uvula and the velum were studied. An anatomic 3D ultrasound view of the fetal secondary palate was obtained at each period of gestation with high anatomic concordance as proved by elevated visualization rates. The overall reliability of visualization across the gestational ages for the major anatomical landmarks of the fetal palate was high (0.74–0.96). The rates of visualization of the uvula and velum varied between 80% and 90%. This anterior axial 3D-view reconstruction of the fetal palate seen by an under side view can provide unique diagnostic information on the integrity of the secondary palate. This technique may become the reference technique in ultrasound investigation of the fetal palate.

Three-Dimensional Ultrasound in Fetal Size and Growth Assessment

We present herein modern three-dimensional (3D) sonographic studies on fetal growth and development, and various fetal volume measurements. The introduction of 3D ultrasound would allow for the assessment of fetal soft tissue deposition, fetal weight estimation, and the volume calculation of fetal organs. With the recent advance in the 3D power Doppler ultrasound as well as the quantitative 3D histogram analysis, quantitative 3D power Doppler in the assessment of the vascularization and the blood flow of the fetal organs and placenta has become feasible. These novel techniques may assist in the evaluation of fetal growth and development, and offer the potential advantages relative to conventional twodimensional fetal growth assessments. 3D ultrasound may be an important modality in future fetal growth and developmental research and in evaluation of fetal growth abnormalities. Keywords: 3D ultrasound, Fetal growth, Soft tissue deposition, Weight estimation, Organ volume measurement

Prenatal assessment of the normal fetal soft palate by three‐dimensional ultrasound examination: is there an objective technique?

To describe a three-dimensional (3D) ultrasound technique for assessing the fetal soft palate. A prospective study conducted from April to December 2006 included 87 fetuses in a low-risk population. Fetal ultrasound scans were performed between 21 and 25 weeks of gestation to determine the normal 3D ultrasound view of the fetal soft tissues of the palate. The sonographers used a 30 degrees-inclined axial 3D view of the fetal palate. Ultrasound images obtained in this view were compared with fetopathological specimens of the same gestational age by two observers, both pediatric surgeons. Each observer indicated whether they thought that the uvula or the velum could be detected, and the differences in responses between the observers were assessed. The frequencies of detection of the uvula and velum of each observer varied between 80% and 90%. The observers showed a significant difference in judging the visualization of the uvula, but not in judging the velum. A 30 degrees -inclined axial 3D ultrasound view seems to be effective in assessing the integrity of the fetal soft palate.

Placental Growth, Angiogenic Gene Expression, and Vascular Development in Undernourished Adolescent Sheep1

Limiting maternal nutrient intake during ovine adolescent pregnancy progressively depleted maternal body reserves, impaired fetal nutrient supply, and slowed fetal soft tissue growth. The present study examined placental growth, angiogenic gene expression, and vascular development in this undernourished adolescent model at Days 90 and 130 of gestation. Singleton pregnancies were established, and ewes were offered an optimal control (C; n = 14) or low (L [0.7 x C]; n = 21) dietary intake. Seven ewes receiving L intakes were switched to C intakes on Day 90 of gestation (L-C). Fetal body weight (P < 0.01) and glucose concentrations (P < 0.03) were reduced in L versus C pregnancies by Day 130, whereas L-C group values were intermediate. Placental cellular proliferation, gross morphology, and mass were independent of maternal nutrition at both Day 90 and 130. In contrast, capillary area density in the maternal caruncular portion of the placentome was reduced by 20% (P < 0.001) at both stages of gestation in L compared with C groups. Caruncular capillary area density was equivalent in the L and L-C groups at Day 130. Placental mRNA expression of five key angiogenic ligands or receptors increased (P < 0.001) between Days 90 and 130 of gestation. VEGFA mRNA expression was higher (P < 0.04) in L compared with C and L-C pregnancies at Day 130, but otherwise gene expression of the remaining angiogenic factors and receptors analyzed was unaffected by maternal intake. Undernourishing the pregnant adolescent dam restricts fetal growth independently of changes in placental mass. Alterations in maternal placental vascular development may, however, play a role in mediating the previously reported reduction in maternal and hence fetal nutrient supply.

Maternal and Fetal Growth, Body Composition, Endocrinology, and Metabolic Status in Undernourished Adolescent Sheep1

The influence of relative maternal undernutrition on growth, endocrinology, and metabolic status in the adolescent ewe and her fetus were investigated at Days 90 and 130 of gestation. Singleton pregnancies to a single sire were established, and thereafter ewes were offered an optimal control (C; n = 14) or low (L [0.7 x C]; n = 21) dietary intake. Seven ewes receiving the L intake were switched to the C intake on Day 90 of gestation (L-C). At Day 90, live weight and adiposity score were reduced (P < 0.001) in L versus C dams. Plasma insulin and IGF1 concentrations were decreased (P < 0.02), whereas glucose concentrations were preserved in L relative to C intake dams. Fetal and placental mass was independent of maternal nutrition at this stage. By Day 130 of gestation, when compared to C and L-C dams, maternal adiposity was further depleted in L intake dams; concentrations of insulin, IGF1, and glucose were reduced; and nonesterified fatty acids increased. At Day 130, placental mass remained independent of maternal nutrition, but body weight was reduced (P < 0.01) in L compared with C fetuses (3555 g vs. 4273 g). Body weight was intermediate (3836 g) in L-C fetuses. Plasma glucose (P < 0.03), insulin (P < 0.07), and total liver glycogen content (P < 0.04) were attenuated in L fetuses. Fetal carcass analyses revealed absolute reductions (P < 0.05) in dry matter, crude protein, and fat, and a relative (g/kg) increase in carcass ash (P < 0.01) in L compared with C fetuses. Thus, limiting maternal intake during adolescent pregnancy gradually depleted maternal body reserves, impaired fetal nutrient supply, and slowed fetal soft tissue growth.

OP09.08: Fetal soft tissue and birth weight: their relationship to newborn infant body composition

Results: A total of 602 organ systems in 260 exams out of 193 patients were identified for this study (26 exams in the first trimester, 161 in the second, and 73 in third trimester). Table 1 shows the total number of organs scanned with 3DUS for each impact group. In the D group, the most significant findings were in these organs: face exams 10, brain 5 and uterine shape 4. In the I group, the most significant findings were in these organs: extremities 16 exams, urogenital system 15, placenta 15 and brain 10. In the V group, the most significant findings were in these organs: face 101 exams, spine 75, extremities 74 and skull 68. In the S group, the most significant findings were in these organs: heart 5 exams, and adnexa 3.

OC104: Soft tissue parameters improve the precision of fetal weight estimation

Objectives: Current weight estimation models do not consider the contribution of fetal soft tissue to fetal weight. We have investigated new weight estimation models that use a combination of conventional biometry and soft tissue parameters. Methods: A cross-sectional study of 248 fetuses was performed using 3DUS to acquire standard biometry (BPD, AC, FDL), fractional arm volume (Avol), and fractional thigh volume (TVol) within 4 days of delivery. Multiple linear regression was used to develop a ‘modified Hadlock’ model (BPD, AC, FDL) and similar models that also included soft tissue parameters for predicting birth weight (BW). New models were prospectively applied in 55 pregnancies. Predicted and observed weights were compared and signed percent differences calculated. Mean and SD of % differences were taken as measures of systematic and random prediction errors, respectively. Proportion of subjects with predicted BW within 5 or 10% (inclusive) were compared using McNemar’s test. Results: For the validation group, the mean maternal age was 27 ± 7.0 (SD) years. Ethnicities included: Caucasian (19), African American (30), Asian (5), Hispanic (1). BW ranged from 390 to 5143 grams (28 males, 27 females). The ‘modified Hadlock’ model was Log BW = 0.0026 (BPD2)+ 0.0467 (AC)+ 0.1865 (FDL) − 0.0042 (AC × FDL)+ 1.346. The best new model was 11.1372 (BPD2 − 67.2281 (BPD) + 1.2175 (AC2)− 17.3004 (AC) − 0.0490 (TVol)+ 25.3052 (TVol) + 285.429.

Inhibiting matrix metalloproteinases with prinomastat produces abnormalities in fetal growth and development in rats

Matrix metalloproteinases (MMPs) play key roles in remodeling of the extracellular matrix during embryogenesis and fetal development. The objective of this study was to determine the effects of prinomastat, a potent selective MMP inhibitor, on fetal growth and development. Prinomastat (25, 100, 250 mg/kg/day, p.o.) was administered to pregnant female Sprague-Dawley rats on gestational days (GD) 6-17. A Cesarian section was carried out on GD 20 and the fetuses were evaluated for viability and skeletal and soft tissue abnormalities. Prinomastat treatment at the 250 mg/kg/day dose produced a decrease in body weight and food consumption in the dams. A dose-dependent increase in post-implantation loss was observed in the 100 and 250 mg/kg/day-dose groups, resulting in only 22% of the dams having viable litters for evaluation at the 250 mg/kg/day dose. Fetal skeletal tissue variations and malformations were present in all prinomastat treated groups and their frequency increased with dose. Variations and malformation in fetal soft tissue were also increased at the 100 and 250 mg/kg/day doses. Prinomastat also interfered with fetal growth of rat embryo cultures in vitro. These data confirm that MMP inhibition has a profound effect on fetal growth and development in vivo and in vitro.

Programmed Healing of Membranous Bone in the Fetal Lamb

In fetal tissues, both soft and hard tissue healing (in long bones) have been found to be scarless. However, healing of membranous bone in the fetal craniofacial skeleton has not been well documented. Pregnant ewes (gestational age range, 80-95 days) underwent a hysterotomy, and fetal lambs had a full-thickness excision of the entire mandibular symphysis region (10 mm). Nonoperated controls were used for comparison (n = 8). After 10 days and 2 weeks, fetuses showed incomplete regeneration of the anterior mandible by examination, computed tomographic scan, and histology. By 4 weeks postoperatively, the mandibular defect had completely closed, but regenerated bony volume was less than control specimens. At 6 weeks postoperatively, the specimen demonstrated complete bony healing without scar or inflammation. Computed tomographic scan measurements for mandibular shape (length over width) was similar in experimental and control specimens. The data indicate that fetal lamb membranous bone defects heal in a scarless fashion and suggest preprogrammed migration of osteogenic tissue.

Individualized growth assessment of fetal soft tissue using fractional thigh volume

The main goals of this study were to introduce fractional thigh volume (TVol) as a new soft tissue parameter for fetal growth evaluation, define its relationship to menstrual age, and develop individualized fetal growth standards based on Rossavik growth models. A prospective, longitudinal study of 22 fetuses was conducted with conventional biometry and TVol measurements by three-dimensional ultrasonography. Infant growth outcomes were determined from modified neonatal growth assessment scores. Rossavik functions (P = c(t)k+s(t)) were used to fit complete datasets to examine relationships between TVol and model coefficients. Second-trimester models were subsequently specified from the linear slopes of growth curves before 28.0 menstrual weeks with each fetus acting as its own control. Third-trimester trajectories and birth measurements were predicted for standard growth parameters and TVol. Observed and predicted measurements were compared using percent deviations and growth potential realization index values. Four additional infants, with serial prenatal scans and postnatal evidence of intrauterine growth restriction (IUGR), were also evaluated. All 22 fetuses had no evidence of growth abnormalities after delivery. Accelerated soft tissue deposition occurred in the fetal thigh by 28 menstrual weeks. A mean TVol start point of 9.0 +/- 1.4 menstrual weeks was consistent with embryological studies of thigh development. Rossavik functions fitted all TVol trajectories well (mean R2 = 0.998 +/- 0.002). By fixing the coefficient k at its mean value (2.976), the fit did not change and the variabilities of coefficients c and s were reduced. The mean percent deviation between observed and predicted third-trimester TVol measurements was -0.048 +/- 7.5%. Relatively early pathological deviations were observed for TVol in all four fetuses with IUGR; in these cases the abdominal circumference was abnormal in only one fetus and thigh circumference in none. Individualized growth assessment can be used to accurately predict TVol during the third trimester of pregnancy and at birth. Expected growth trajectories, from second-trimester data, do not rely on population-based standards because each fetus serves as its own control. This new parameter may allow earlier detection and improved monitoring of fetal soft tissue abnormalities such as IUGR.

Teratogenic vulnerability of Wistar rats to diphenyl ditelluride

The effect of single maternal subcutaneous (s.c.) injection of 0.12 mg/kg diphenyl ditelluride, (PhTe)2, diluted in canola oil at days 6, 10 or 17 of gestation were evaluated in Wistar rats. The reduction of body weight gain was statistically significant at GD9, for the dams that received (PhTe)2, at GD6; at GD13, for the dams that received (PhTe)2, at GD10, and at GD20, for the dams that received (PhTe)2, at GD17, when compared to respective control groups. External and internal fetal soft tissues examination was performed on day 20 of gestation. Single maternal injection at day 10 of gestation resulted in appearance of malformation in fore- and hind-limbs, absent or short tail, subcutaneous blood clots, exophthalmia, hydrocephalus and absence of the cranial bone and cutaneous tissue in fetuses on day 20 of gestation. Besides, (PhTe)2 reduced fetal body and cerebral weight, kidney length, measurements of body dimension and provoked 73% of fetal mortality. Subcutaneous administration of (PhTe)2 on day 17 of gestation was associated with 94% mortality, hydrocephalus and edema. Histological evaluations of fetal brain demonstrated displaced brain tissue with absence of the cranial bone and cutaneous tissue when diphenyl ditelluride was administered in GD10. Histological evaluation of fetal head exposed at GD17 revealed a decrease of the brain volume with consequent dilation of the lateral ventricles and the adjacent tissues were thinner than that of control group tissues. No fetal changes were observed after administration of (PhTe)2 at day 6 of gestation. Thus, (PhTe)2 can be teratogenic to rat fetuses and toxic for dams. The late fetal stages of rat prenatal development appeared uniquely sensitive to organic tellurium exposure.

The fetal body compartments and their detection during pregnancy. A review.

The recent efforts in the study of fetal compartments could help us to a better recognition of the proper fetal growth and well being. Fat content correlates directly with energy stores. Fat mass and lean body mass is often used in the nutritional assessment of the individual. Moreover chromosomal abnormalities may be detected by studying the fetal soft tissues of the neck, thus providing further proofs of the importance of evaluating the fetal body compartments. To obtain fat mass and lean mass, several measurements were proposed. We report a review of the literature on that topic.

P197: Fractional thigh volume: a new soft tissue parameter for fetal growth assessment

Previous attempts to quantify fetal soft tissue by conventional sonography have been difficult. Fractional thigh volume measurements, obtained by three-dimensional ultrasonography (3DUS) were evaluated for this purpose, using Individualized Growth Assessment (IGA). Longitudinal sonographic studies of normal fetuses were performed to obtain standard biometry and fractional thigh volumes. Fractional thigh volumes were based on 50 percent of the femoral diaphysis length. Start points, the theoretical age at which an anatomical parameter can first be identified, were calculated from linear functions relating the cube root of fractional limb volume to menstrual age prior to 28.5 weeks'. Regression analysis was used to fit Rossavik functions (P = c(t) k + s(t), where P is the anatomic parameter, t is menstrual minus start point, and c, k, s are model coefficients) to individual growth trajectory data. Rossavik models specified from the linear slopes of growth curves before 28.5 weeks were used to predict TVol during the third trimester and at birth. Neonatal growth status was determined from anatomic measurements and 3DUS within 48 hours of delivery. 22 fetuses (14 females, 8 males) were prospectively studied between 17.4 and 39.3 weeks, menstrual age. The mean birthweight was 3296 ± 253 (SD) grams. All neonates had normal modified Neonatal Growth Assessment Scores. The mean start point (9.0 ± 1.4 weeks') was consistent with completion of thigh development at 8.5 weeks', determined from embryological studies. Rossavik models fit the TVol trajectories very well (mean R2 = 99.8 ± 0.2). By fixing the k coefficient at its mean (2.976), the fit did not change and the variabilities of coefficients c and s were reduced. The mean percent deviation between observed and predicted TVol measurements was − 0.048 ± 7.5% (n = 72) during the third trimester. Neonatal TVol measurements in 12 infants, corrected for systematic error (− 16.7%) led to an averaged signed deviation of − 1.8 ± 9.2% from predicted values. IGA standards for fractional thigh volume provide a new approach for characterizing soft tissue growth. Normal growth trajectories and neonatal soft tissue volume can be accurately predicted from growth models specified by fractional thigh volume data obtained before 28.5 menstrual weeks. The normal variability for these predicted TVol measurements is about one-third of what has been reported for fetal thigh circumference. This parameter may allow earlier detection and improved monitoring of fetuses with soft tissue abnormalities such as IUGR and macrosomia.

Three‐dimensional sonographic evaluation of fetal soft tissue deposition

Objectives: To evaluate fetal nutritional status in utero and to detect intrauterine growth restriction and macrosomia by use of three‐dimensional ultrasonography.Methods: Fifty‐two fetuses from 28 to 41 weeks gestation were studied within 1 week before delivery using a transabdominal three‐dimensional transducer. The fetal nutrition score values were determined from a qualitative assessment of the amount of subcutaneous tissue present at three locations (face, ribs, and buttocks) on the antenatal three‐dimensional ultrasonograms. Fetal nutritional status, using fetal nutrition score, was compared with those by modified neonatal nutrition score and ponderal index, respectively.Results: There was a significant linear correlation between fetal nutrition score and modified neonatal nutrition score. Fetal or neonatal nutrition score correlated well with birth weight and neonatal crown‐heel length, respectively. However, no significant correlation between ponderal index and fetal nutrition score or modified neonatal nutrition score was evident. Ponderal index also did not correlate with birth weight and neonatal crown‐heel length, respectively.Conclusion: We do cast doubt on the usefulness of the ponderal index for measurement of neonatal soft tissue and muscle mass. Fetal nutrition score using three‐dimensional ultrasonography provides a novel means of evaluating the nutritional status of the fetus in utero, and should be useful for predicting the extreme in fetal growth earlier.

Effect of transplantation of human fetal tissues on prooxidant-antioxidant equilibrium in the liver and blood rats after partial hepatectomy in rats.

We studied the effect of transplantation of fetal liver cells and postnuclear cytoplasmic fraction from human fetal soft tissues on the prooxidant-antioxidant equilibrium in the liver and blood of rats after partial hepatectomy. The preparations increased antioxidant activity and decreased the intensity of lipid peroxidation, which probably contributes to their therapeutic effects.

Optimisation of the biology of soft tissue repair

As identified in this review, over the past twenty years there have been a number of very exciting new developments in the quest to optimise soft tissue repair. Comparing fetal soft tissue injuries, which heal by regeneration, to the adult processes of healing by inflammation-induced scar formation has led to a number of insights into how the latter may be improved. Seeding wounds with embryonic stem cells, bridging gaps with cell-derived "engineered tissues", addition of exogenous hyaluronic acid and modification of wounds to either enhance the growth factors which have been implicated in regeneration (e.g. TGF-B3) or block those implicated in scar formation (eg. TGF-B1) have all shown promise. Our group has quantified numerous cellular, molecular, biomechanical and matrix abnormalities of scar in a rabbit model of ligament healing. Based on these studies which we review here, three matrix deficiencies have been identified which appear to have specific implications to scar weakness: organisational "flaws", abnormal hydroxypyridinoline collagen cross-link densities and abnormally small, slow-maturing collagen fibrils. In tests aimed at finding therapeutic solutions in this model, the addition of a 7ug bolus of TGF-B1 at day 21 or 2.5ng/day of TGF-B1 being pumped into a wound x 21 days increased the size of ligament scars but did not improve their material strength. It also did not alter any of the above-noted matrix deficiencies. A liposome-mediated anti-sense gene therapy approach aimed at decreasing the expression of the proteoglycan decorin in 21-day scars, however, has significantly increased the size of scar collagen fibrils as well as improved these scars mechanically. Based on these positive results from a single dose of only one targeted molecule, we believe that this gene therapy approach has great potential for further scar improvement. If combined with some of the other biological strategies reviewed above, a repair which is closer to true regenerative healing of ligaments, and all soft tissues, may eventually be achieved.

Latissimus dorsi flap procedures to cover myelomeningocele in utero: A feasibility study in human fetuses

There is experimental and clinical evidence that in utero repair of myelomeningocele (MMC) may preserve neurological function. In five aborted human fetuses (gestational age, 18 to 29 weeks), the authors tested whether proximally and distally based latissimus dorsi flaps (LDF) can be used to cover MMC lesions. Fetal soft tissues were developed enough to allow surgical handling, preparation of both flap types was technically easy, and the vascular pedicles could be preserved. The proximally pedicled LDF was suitable to cover the upper spine from lower cervical to lower thoracic levels, whereas the distally pedicled LDF was suitable to cover the spine between lower thoracic and lower sacral levels. These results suggest that various LDF procedures are technically feasible in early gestational human fetuses and could be used for in utero repair of MMC.

Fetal nonmuscular soft tissue: a prenatal assessment.

In this study, the fetal nonmuscular soft tissue is evaluated prenatally in 52 uncomplicated singleton pregnancies at 36 weeks of gestation or later. The means and standard deviations of the NMST at the midarm region and the ratio of NMST to HL are 6.0 +/- 1.0 mm and 0.08 +/- 0.02, respectively. No correlation was seen between the NMST and birth weight.

Studies on the prenatal toxicity of toluene in rabbits following inhalation exposure and proposal of a pregnancy guidance value.

Prenatal toxicity of toluene was determined in two separate studies by inhalation exposure of Himalayan rabbits. In the first study 15 artificially inseminated females per group were exposed to 30, 100, or 300 ppm and in the second study 20 artificially inseminated females per group inhaled 100 or 500 ppm. In each case the rabbits were exposed for 6 hours per day from day 6 post-insemination (p.i.) to day 18 p.i. The respective controls inhaled conditioned clean air under the same exposure conditions. No signs of maternal toxicity were observed. All data obtained on gestational parameters were found to be within the variation range reported for this rabbit strain. The fetal external, soft tissue and skeletal findings were seen in toluene exposed fetuses in a frequency similar to the corresponding and/or historical controls. Differences observed between the groups were not concentration dependent and were considered incidental rather than compound related. Therefore, toluene was not embryotoxic, fetotoxic, or teratogenic for rabbits exposed during the period of organogenesis. The highest concentration tested under these conditions (500 ppm) was found to be a no-observable-adverse-effect level (NOAEL) for both the adult and the fetal Himalayan rabbit. Based on these and previous results of animal studies of prenatal toxicity, a safety or uncertainty factor approach is considered for setting limits of exposure for women at workplaces. A pregnancy guidance value of 20 ppm is proposed.