Recombinant vascular endothelial growth factor 121 injection for the prevention of fetal growth restriction in a preeclampsia mouse model.

AIM: To discover the potential role of recombinant VEGF121 (rVEGF121) injection for the prevention of fetal growth restriction in a preeclampsia (PE) mouse model (Mus musculus). SUBJECTS AND METHODS: This is an experimental study of 30 pregnant mice that were randomly divided into three groups: normal, PE, and PE with rVEGF121 injection. The PE mouse model was created by injecting anti Qa-2 10 ng iv, which is deleterious to Qa-2 expression (homologous to HLA-G), from the first to the fourth day of gestation. PE was validated by measuring serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor(PIGF) and also by kidney histopathology. Recombinant VEGF121 was given on the ninth day until the 11th day of pregnancy; mice were terminated on the 16th day. Fetal weights were acquired with a Denver analytical balance. Serum levels of sFlt-1 and PlGF were measured using enzyme-linked immunosorbent assay (ELISA). The data were statistically analyzed via analysis of variance (ANOVA). RESULTS: On average, fetal birth weight was 0.7150 g in the normal group, 0.4936 g in the PE group, and 0.6768 g in the PE with rVEGF121 injection group. ANOVA showed significant growth restriction in the PE group (P=0.006), confirming the use of anti Qa-2 as a suitable PE model. Kidney histopathology results, sFlt-1 levels, and PlGF levels also demonstrated that anti Qa-2 consistently conferred hallmarks of PE in mice. Vascular endothelial growth factor (VEGF) injection prevented fetal growth restriction; comparable fetal weights were observed between the PE model with VEGF treatment and the normal group (P=0.610) but differed from the untreated PE group (P=0.021). CONCLUSIONS: Injection of rVEGF121 has the potential to prevent fetal growth restriction in a newly proposed PE mouse model.

Influence of antenatal magnesium sulfate application on cord blood levels of brain-derived neurotrophic factor in premature infants.

AIM: To investigate the influence of antenatal magnesium sulfate (MgSO4) application on cord blood brain-derived neurotrophic factor (BDNF) levels - the first-line neuroprotection for preventing cerebral palsy in prematurely born infants. SUBJECTS AND METHODS: A randomized controlled trial was conducted by observing 72 pregnant women who were divided into three groups: group I (preterm pregnancy with MgSO4), group II (preterm pregnancy without MgSO4), and group III (full-term pregnancy as control group). Groups I and II were selected by block permutation randomization on subjects. Inclusion criteria consisted of preterm pregnancy at 34 weeks of gestation or less who were in labor or having planned terminations and receiving antenatal corticosteroids. Exclusion criteria consisted of previous complications caused by MgSO4, previous history of antenatal MgSO4 application in the current pregnancy infant was born before 4 h administration of MgSO4 or unborn more than 72 h after maximum course of antenatal MgSO4 of 24 h, prolonged antenatal MgSO4 treatment (>24 h), refusal to participate, and emergent adverse events during the study. Group I was given intravenous MgSO4; initial dose was 4 g, which was maintained at 1 g/h up to maximum of 24 h. Meanwhile, groups II and III were not given any special treatment. BDNF was examined by ELISA by taking 5 mL cord blood sample shortly after birth. The result was statistically measured by ANOVA. RESULTS: The cord blood BDNF levels in premature infants with antenatal MgSO4 was significantly higher than in premature infants without antenatal MgSO4 (11,568 vs. 5027 pg/mL, P=0.000). Moreover, the result was statistically comparable to full-term infants (11,568 vs. 13,300 pg/mL, P=0.085). CONCLUSION: The application of antenatal MgSO4 in preterm delivery increased cord blood BDNF levels, which could have a potential role on fetal neuroprotection. Further investigation is needed.

New scoring system for fetal neurobehavior assessed by three- and four-dimensional sonography.

AIM: To produce a new scoring system for fetal neurobehavior based on prenatal assessment by 3D/4D sonography. We identified severely brain damaged infants and those with optimal neurological findings and compared fetal with neonatal findings. RESULTS: The new scoring system was retrospectively applied in a group of 100 low-risk pregnancies. After delivery, postnatal neurological assessment was performed, and all neonates assessed as normal reached a score between 14 and 20, which we assumed to be a score of optimal neurological development. Subsequently, the same scoring system was applied in the group of 120 high-risk pregnancies in which, based on postnatal neurological findings, three subgroups of newborns were found: normal, mildly or moderately abnormal, and abnormal. Normal neonates had a prenatal score between 14 and 20, mildly or moderately abnormal neonates had a prenatal score of 5-13, whereas those infants who were assigned as neurologically abnormal had a prenatal score from 0-5. CONCLUSION: A new scoring system for the assessment of neurological status for antenatal application is proposed, similar to the neonatal optimality test of Amiel-Tison. This preliminary work may help in detecting fetal brain and neurodevelopmental alterations due to in utero brain impairment.

How useful is 3D and 4D ultrasound in perinatal medicine?

AIM: The purpose of this paper is to review and analyze the published literature on the use of three-dimensional (3DUS) and four-dimensional (4DUS) ultrasound in perinatal medicine. METHODS: We systematically searched Medline through PubMED (January 2000-January 2006), including EMBASE/Excerpta Medica database as well as the Cochrane Database of Systematic Reviews. The search terms used to identify clinical application of 3DUS and 4DUS studies in perinatal medicine were technical development, special features, and recommendation for fetal imaging, research on 3DUS or 4DUS, and the usage of invasive 3DUS or 4DUS procedures. The reference bibliographies of relevant books were also manually searched for supplementary citations. Inclusion criteria were as follows: (1) studies related to the use of 3DUS or 4DUS in perinatal medicine; (2) full text were available in English; (3) publication format of original scientific articles, case reports, editorials or literature reviews and chapters in the books. RESULTS: Five hundred and seventy-five articles were identified, and among those, 438 were relevant to this review. CONCLUSIONS: 3DUS and 4DUS provided additional information for the diagnosis of facial anomalies, evaluation of neural tube defects, and skeletal malformations. Additional research is needed to determine the clinical utility of 3DUS and 4DUS for the diagnosis of congenital heart disease, central nervous system (CNS) anomalies and detection of fetal neurodevelopmental impairment assessed by abnormal behavior in high-risk fetuses.

Three- and four-dimensional ultrasonography for the structural and functional evaluation of the fetal face.

Ultrasonographic examination of the fetal face can provide information that may lead to the diagnosis of anomalies in other organs or systems. Thus, the fetal face represents a "diagnostic window" for fetal diseases and syndromes. Three-dimensional ultrasonography (3DUS) improves the evaluation of anatomic fetal facial anomalies over what is possible by 2-dimensional ultrasonography (2DUS). Four-dimensional ultrasonography (4DUS), by adding the temporal component to the examination, allows visualization of facial expressions that might be useful in the study of fetal behavior and maternal-fetal bonding. In this article, we evaluate the potential of 3D/4DUS for the study of structural and functional development of the fetal face.

The assessment of fetal behavior of growth restricted fetuses by 4D sonography.

AIM: To find out whether the quantity of fetal facial expression and quality of body movements can be used as an additional diagnostic criterion for prenatal brain impairment in fetuses with growth restriction. SUBJECT AND METHODS: A prospective study was conducted in 50 uncomplicated healthy women as control group with reliably dated pregnancies and 50 pregnant women with a growth restricted fetus as study group in the third trimester of pregnancy. 4D ultrasound observation is specially designed to assess whether functional brain impairment and fetal growth restriction had prenatally occurred by the utilization of several behavioral patterns. RESULTS: The median value of all movement patterns in the normal fetuses differed from fetuses with intrauterine growth restriction (IUGR). Statistical evaluation revealed significant differences in the distribution of the movements between these groups (P<0.05). We noted a tendency that IUGR fetuses have less behavioral activity than normal fetuses in all observed movement patterns. Correlation reached statistical significance between normal and IUGR fetuses in the third trimester in hand to head, hand to face and head retroflexion. Statistically significant differences could be shown in the distribution of the median values of observation over the five qualitative categories of head and hand movements (P<0.05). CONCLUSIONS: Recent data on IUGR fetuses obtained by 4D sonography are stimulating and might result in a more effective strategy to assess development before birth. The results of this study may encourage future use of 4D ultrasound for quantitative and qualitative assessment of fetal behavior as possible indicators of the neurological condition in IUGR fetuses.

Normal standards for fetal neurobehavioral developments--longitudinal quantification by four-dimensional sonography.

AIM: To construct normal standards for fetal neurobehavioral development using longitudinal observations through all trimesters by four-dimensional sonography. SUBJECT AND METHODS: A group of 100 healthy normal singleton pregnancies were recruited for longitudinal 4D US examinations to evaluate fetal neurodevelopmental parameters between 7 to 40 weeks' gestation. Variables of maternal and fetal characteristics including gestational age, eight fetal movements patterns in the first trimester and 14 parameters of fetal movement and fetal facial expression patterns recorded thereafter for the construction of fetal neurological charts. RESULTS: Measurement of 7 parameters in the first trimester and 11 parameters in the second and third trimesters correlated with gestational age (P<0.05). Those parameters have been followed longitudinally through all trimesters and showed increasing frequency of fetal movements during the first trimester. A tendency towards decreased frequency of facial expressions and movement patterns with increasing gestational age from second to third trimesters has been noticed. CONCLUSION: With 4D sonography, it is possible to quantitatively assess normal neurobehavioral development. There is urgent need for further multicentric studies until a sufficient degree of normative data is available and the predictive validity of the specific relationship between fetal neurobehavior and child developmental outcome is better established.

New data about embryonic and fetal neurodevelopment and behavior obtained by 3D and 4D sonography.

The development of the human central nervous system (CNS) begins in the early embryonic period and proceeds through a sequence of very complicated processes long after delivery. Although the neurodevelopmental processes are genetically determined, their complexity and intensity implicates the vulnerability of the CNS to number of environmental factors. There is substantial evidence to show that many neurological problems, from minor cerebral dysfunction to the cerebral palsy, originate form the prenatal, rather than perinatal or postnatal periods of life. A variety of neurological and neuropsychiatric diseases is nowadays considered to originate, at least partly, from the prenatal incidents. In most of these conditions, there is no reliable parameter for detection or prediction of cerebral lesions and there is an urgent need to develop strategies that would enable the early detection of cerebral lesions or indications that such lesions might occur. The new, advanced, imaging techniques such as 3-dimensional and 4-dimensional sonography, opened a new perspective for the investigation of structural and functional development of fetal CNS. The application of these techniques might improve our understanding of the prenatal neurodevelopmental events and possibly facilitate the development of diagnostic strategies for early detection or prevention of brain dysfunctions and damage.

Structural and functional early human development assessed by three-dimensional and four-dimensional sonography.

OBJECTIVE: To summarize the role of three-dimensional and four-dimensional ultrasound in the assessment of early human development. DESIGN: Review of literature. SETTING: Ultrasound research center and obstetrics and gynecology department in a tertiary care facility. RESULT(S): The introduction of high-frequency transvaginal tranducers has resulted in remarkable progress in ultrasonographic visualization of early embryos and fetuses and the development of sonoembryology. Furthermore, recent introduction of three-dimensional and four-dimensional ultrasounds combined with the transvaginal approach has produced more objective and accurate information on embryonal and early fetal development. For the first time parallel analyses of structural and functional parameters in the first 12 weeks of gestation become possible. CONCLUSION(S): The anatomy and physiology of placental and embryonic development is a field where medicine exerts its greatest impact on early pregnancy at present time, and it opens fascinating aspects of embryonic differentiation. Clinical assessment of those stages of growth rely heavily on three-dimensional and four-dimensional sonography, one of the most promising forms of noninvasive diagnostics today and embryological phenomenon, once matters for textbooks are now routinely recorded with outstanding clarity.

The assessment of fetal behavior in early pregnancy: comparison between 2D and 4D sonographic scanning.

AIM: To determine the accuracy of 4D sonography in the assessment of embryonic and early fetal motor activity in the first trimester of normal pregnancy, in comparison to the 2D sonography. METHODS: Fifty pregnant women between 6-14 weeks of gestation with singleton pregnancy were assigned for the investigation. Two dimensional and four dimensional recordings were displayed on the screen and recorded on the videotape during the 15 minutes observation period. RESULTS: General body, head and limb movements recorded by 2D sonography were notable by 4D technique in the same gestational age. These movements were presented collectively with maximum, minimum, and median frequencies during 15 minutes observation period. Spearman rank order correlation reached statistical significance (P<0.05) between the frequencies of all observed movement patterns assessed by two different techniques. Several movement patterns, such as sideway bending, hiccup, breathing movements, mouth opening and facial movements could be observed only by 2D sonographic technique in this period of gestation. CONCLUSION: Presently, both 2D and 4D methods are required for the assessment of early fetal motor development and motor behavior. It is reasonable to expect that such technological improvement may provide some new information about the intrauterine motor activity and facilitate the prenatal detection of some neurological disorders.

Fetal behavior assessed in all three trimesters of normal pregnancy by four-dimensional ultrasonography.

AIM: To assess fetal behavior in all three trimesters of normal pregnancy and to investigate the continuation of behavior from fetal to neonatal period. METHODS: One hundred out of 130 pregnant women in all trimesters with singleton pregnancy were assigned for the investigation. All recordings were performed in the morning, after two hours of fasting. Video recordings of newborns were made while the newborns were in bed, separated from other infants in the nursery, dressed, and lying on their backs in a supine position with unrestrained hands. Recording was not performed during prolonged episodes of fussing and crying, during drowsiness, and episodes of hiccupping. All observed facial expressions and movement patterns were presented collectively with maximum, minimum, and median frequencies during 30-minute observation period. RESULTS: We noted a tendency towards decreased frequency of facial expressions and movement patterns with increasing gestational age. In the first trimester, we observed the highest incidence of general movements ranging between 5 and 147, and with a median value of 47. In the second trimester, the number of head and hand movements decreased gradually, compared with the first trimester. The highest range was registered for head retroflexion pattern, ranging from 15 to 42 with a median of 25. The most frequent facial pattern in the second trimester was sucking (3 and 30 movements per infant with a median value of 9). Wilcoxon rank-sum test showed statistically significant differences between the fetuses in the third trimester and the newborns (P<0.05) in hand to head, hand to mouth, hand to eye, hand to ear movement), tongue expulsion, and smiling, whereas the differences between the rest of the movements were not statistically significant. Spearman rank order correlation reached statistical significance (P<0.05) in isolated eye blinking, smiling, grimacing, hand to head, hand to mouth, hand to eye, hand to face, and in hand to ear movement, whereas the differences between the rest of the facial expressions were not statistically significant. CONCLUSION: Fetal behavioral patterns directly reflect the developmental and maturational processes of the central nervous system. 4D observation of fetal and early neonatal period may add to better understanding of the neurological development of the fetus.

Behavior of an anencephalic fetus studied by 4D sonography.

Diagnosis of anencephaly during early pregnancy by ultrasound which is based on the demonstration of absent cranial vault and cerebral hemispheres, has been known for more than 25 years. Morphological records of abnormal and normal brain structure in anencephalic fetuses have been clearly understood. Nevertheless, there are still unknown facts about fetal behavior affected by anencephaly. Although abnormal motor behavior in anencephalic fetuses has been reported, detailed quantitative and qualitative study of the fetal behavior assessed by direct four-dimensional (4D) ultrasound does not exist. In the present case, we describe a comparison of fetal behavior between a fetus with anencephaly and a normal fetus at 19 weeks of pregnancy.

Behavioral pattern continuity from prenatal to postnatal life--a study by four-dimensional (4D) ultrasonography.

AIM: To investigate whether the same behavioral patterns were present pre- and postnatally, and whether there were any differences in the frequency of movements observed in fetal and in early neonatal life. SUBJECTS AND METHODS: Ten out of 37 pregnant women in the third trimester of pregnancy (median gestational age 34 weeks, range 33 to 35 weeks) in the two-month period (from November 1st to December 31st, 2003) were enrolled in the investigation. Ten term, appropriate for gestational age newborns (seven born vaginally, three by elective SC, six girls, six first-born) and were enrolled in the study. All 4D examinations were performed on Voluson 730 (Kretztechnik, Zipt, Austria) and Acuvix (Medison, Korea) with transabdominal 5 MHz transducer. After standard assessment in 2D B-mode ultrasound, a 4D mode was switched on and live 3D image was reconstructed by selecting the ideal representative 2D image placed in the region of interest (ROI). The recordings of neonatal behavior were made on the Sony P-612 OHMPL videotape by video camera (Sony Camcoder CC DTRV 318 Hv8) and reviewed on the videocassette recorder (Sony VHS SLV-N 900). The median of newborns' age at the moment of recording was 49 hours (range 4 to 112). During the examination, newborns were lying in the bed, separated from other infants in the nursery, dressed, and lying on their backs in a supine position with unrestrained hands. The temperature in the room was 22 to 24 degrees C. The video recording was performed mainly while the children were actively awake or during alert inactivity. RESULTS: There were no movements observed in fetal life that were not present in neonatal life, while the Moro reflex was present only in neonates. The most frequent fetal and neonatal movements were scowling, eye and mouth opening, and hand to face, hand to eye and hand to head movements. Isolated blinking, mouth to eyelid movement, yawning, tongue expulsion and scowling were more frequent in neonates than in fetuses, although the difference was not statistically significant. Hand to mouth movements were more frequent in neonatal than in fetal life while all other hand movements were less frequent in neonates than in fetuses, although the differences did not reach statistical significance. Spearman rank order correlation reached statistical significance in smiling (R=0.71; t=2.91; P=0.02) and in hand to ear movement (R = 0.80; t= 3.86; P = 0.005), and was almost statistically significant in isolated eye blinking (R=0.61; t=2.17; P =0.06), while the correlations between the rest of the movements were not statistically significant. CONCLUSIONS: 4D ultrasonography is a powerful tool in the assessment of fetal behavior, and our study showed that there is a continuity from fetal to neonatal behavior, especially in terms of isolated eye blinking movements, mouth and eyelid opening, yawning, tongue expulsion, smiling, scowling and hand movements directed to other parts of the face.