Human Reproduction, Vol. 15, No. 6, 1407-1412,
June 2000
© 2000 European Society of Human Reproduction and Embryology
Intrauterine sonographic measurement of embryonic brain vesicle
Departments of Perinatology, Kagawa Medical University, 1750–1 Ikenobe, Miki, Kagawa 761-0793, Japan
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Abstract |
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Our purpose was to evaluate embryonic brain vesicle measurements using intrauterine sonography in early first-trimester pregnancy. Fifty-one women about to undergo therapeutic abortion from 7–9.9 weeks gestational age were studied with a specially developed flexible catheter-based high-resolution real-time miniature (2.4 mm in outer diameter) ultrasound transducer (20 MHz). Length, width and height of telencephalon, diencephalon, mesencephalon and rhombencephalon were measured. The normal range of embryonic brain vesicle measurements for each day of pregnancy was determined. Curvilinear relationships were found between the menstrual age and telencephalon height (r2 = 71.2%), diencephalon length (r2 = 39.6%), width (r2 = 39.4%) and height (r2 = 48.3%) and mesencephalon length (r2 = 59.0%) respectively. Linear relationships were found between the menstrual age and telencephalon width (r2 = 41.4%), mesencephalon height (r2 = 58.7%) and rhombencephalon length (r2 = 44.9%), width (r2 = 56.8%) and height (r2 = 35.5%) respectively. Telencephalon length and mesencephalon width were constant throughout menstrual age. These results suggest that intrauterine sonography provides accurate embryonic brain measurements in utero. Moreover, intrauterine sonography may become an important modality in future embryological research and in detection of embryonic brain developmental disorders in early first-trimester pregnancy.
Key words: brain vesicle/embryo/growth/intrauterine ultrasonography
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Introduction |
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The neural tube cranial to the fourth pair of somites develops into the brain. During the fourth week three primary brain vesicles form: the forebrain, or prosencephalon, the midbrain, or mesencephalon and the hindbrain, or rhombencephalon. During the fifth week, the forebrain partly divides into two vesicles, the telencephalon and the diencephalon, and the hindbrain partly divides into the metencephalon and the myelencephalon. As a result, there are five secondary brain vesicles (Moore, 1982
; Harkness and Baird, 1997). There have been only two reports on the growth of the fetal brain vesicle measured by transvaginal sonography in the early first-trimester pregnancy (Blaas et al., 1994, 1995a). In those two investigations, image quality using transvaginal sonography was not very high. In the first investigation (Blaas et al., 1994), mathematical functions were not presented and descriptive statistics were not conducted in either of the investigations (Blaas et al., 1994, 1995a).
Flexible catheter-based high-resolution real-time ultrasound transducers have been developed for use in visualization of anatomical structures of the normal human embryo (Ragavendra et al., 1991, 1993). Fujiwaki et al. (1995) demonstrated that intrauterine sonography could reveal embryonic structures 1–3 weeks earlier than transvaginal sonography (Fujiwaki et al., 1995). Moreover, it was possible to obtain finer image quality of very small embryonic structures with intrauterine sonography than with transvaginal sonography (Hata et al., 1997a). There have been a few reports on embryonic organ measurements by intrauterine sonography in the early first-trimester pregnancy (Hata et al., 1996, 1997b). The objective of the current study was to evaluate embryonic brain vesicle growth at early first-trimester gestation with the use of intrauterine sonography with a flexible catheter-based high-resolution real-time miniature transducer.
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Materials and methods |
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A total of 51 women (20 at week 6, 18 at week 7 and 13 at week 8), about to undergo therapeutic abortion at between 7 and 9.9 weeks gestational age, was studied with specially developed catheter-based high-resolution real-time miniature (2.4 mm in outer diameter) ultrasound transducers [20 MHz (Aloka AMP-PN20-08L®; Aloka Co., Tokyo, Japan)]. Under Japanese law, a normal pregnancy can be terminated if neither parent wishes it to continue, or if maternal health or family is threatened. In this study, all pregnancies were terminated for these reasons and were therefore considered to be normal. Subjects were randomly recruited for a 10 month period commencing September 1998. The depth of penetration of the ultrasound beam was ~2 cm. The ultrasonic catheter was connected to an ultrasound device (Aloka SSD-550®; Aloka Co.). A motor in the main imaging device (Aloka ASU-100®; Aloka Co.) rotated the metal drive shaft at 900 r.p.m., resulting in a 360° real-time grey-scale image orientated perpendicularly to the long axis of the ultrasonic catheter. All examinations were performed by one examiner (H.T.). The intra-observer coefficient of variation for the measurement of each brain vesicle parameter was <10%. The study was approved by the local ethical committee of Kagawa Medical University and standardized informed consent was obtained from each patient.
Before each procedure, the intrauterine location of the embryo was confirmed by transvaginal sonography. Each patient was prepared and draped in the usual sterile fashion in the dorsolithotomy position. A sterile speculum was inserted into the vagina. The ultrasonic catheter was introduced gently through the cervix and into the endometrial cavity until it could not be advanced any further. Once within the endometrial cavity, the catheter tip was advanced or withdrawn slightly until the embryo was visualized.
The gestational age by menstrual history was compared with that by the crown–rump length (CRL) (Iwamoto, 1983; Coulam et al., 1996; Harkness et al., 1997). Only those cases with a discrepancy <±3 days were included in the study.
The methods used to obtain embryonic brain measurements have been described in detail elsewhere (Blaas et al., 1994, 1995a). Essentially, in the sagittal midline section, the length and height of the cavities of the mesencephalon and the diencephalon were obtained (Figure 1). In a transverse section, the widths of the mesencephalon and diencephalon cavities and the telencephalon were measured (Figure 2). The length of the telencephalon was measured in a parasagittal section as the longest possible distance from the anterior to the posterior border of the cortex (Figure 3). The height was measured over the frontal horn, not including the basal ganglia. The planes for the measurement of the length and width of the rhombencephalon cavity are shown in Figure 4. In the sagittal midline section (Figure 5), the depth of the rhombencephalic cavity was measured from the pontine flexure to the roof of the fourth ventricle. The dataset contained only one measurement per patient to provide a cross-sectional analysis. After database screening with tests for a normal distribution, a growth curve for the brain vesicle parameter was determined for the cross-sectional data. Dataset regression analysis was carried out, testing the regression of brain vesicle measurements on menstrual age using polynominals of the first through the third degree (Dunn and Clark, 1974; Rohatgi, 1976; Bertagnoli et al., 1983). The different methods were tested and independent variable deletion carried out by analysis of variance applied to the regression, followed by calculation of the step-down method coefficients (Snedecor and Cochran, 1967). The choice of the optimal model was based on the following criteria: largest r2, all coefficients different from 0 and low standard deviation of regression (SDR) (Bertagnoli et al., 1983). Pathological examination, chromosome analysis and brain vesicle and CRL measurements post abortum could not be done, because the embryos were damaged during the therapeutic abortion.
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Results |
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There was no difficulty in passing the imaging catheter through the cervix into the endometrial cavity. Neither bleeding nor leakage of amniotic fluid from the external cervical os was seen after removal of the catheter. There were no known immediate complications.
Two cases (one each at week 6 and 7) were excluded from the study because of the shallow scanning range of high-frequency transducers or inappropriate embryonal position. Nine cases (three at week 6, four at week 7 and two at week 8) were excluded from the study because the discrepancy between the gestational age by menstrual history and that by the CRL was >3 days.
Curvilinear relationships were found between the menstrual age and telencephalon height, diencephalon length, width and height and mesencephalon length respectively (Table I). Linear relationships were found between the menstrual age and telencephalon width, mesencephalon height and rhombencephalon length, width and height respectively (Table I). Telencephalon length and mesencephalon width were constant throughout menstrual age (Table I). The normal ranges of embryonic brain vesicle measurements for each day of pregnancy were determined (Tables II, III, IV and V).
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Discussion |
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When viewed by means of intrauterine sonography with a flexible catheter-based high-resolution real-time miniature transducer (Hata, 1999
), the brain vesicles were the most prominent organs at each week and were seen as multilobular consecutive anechoic structures. At week 5, the parallel lines of the neural tube could only be noted. Half of the embryos studied during the first 7 weeks still had primary brain vesicles, which represented the unpartitioned prosencephalon and the rhombencephalon. Half of the embryos during the first 7 weeks and most embryos and all fetuses after week 7 had five secondary brain vesicles (telencephalon, diencephalon, mesencephalon, metencephalon and myelencephalon). Fujiwaki et al. (1995) demonstrated that intrauterine sonography could reveal embryonic structures 1–3 weeks earlier than transvaginal sonography. Moreover, it was possible to obtain finer image quality of very small embryonic structures with intrauterine sonography than with transvaginal sonography (Hata et al., 1997a). Therefore, intrauterine sonography can become a useful modality for precise measurement of very small embryonic structures. Our previous studies (Fujiwaki et al., 1995; Hata et al., 1997a) also suggested that intrauterine sonography with high-resolution transducers might be suitable for gestation week 5, 6, 7 or 8 examinations.
It seems that intrauterine sonography lacks either the manoeuvrability, deep beam penetration or ability to allow perpendicular planes of section to be obtained. The ultrasound measurements of small embryonic structures are associated with an elevated intra-observer variability (Blaas et al., 1994, 1995a). In this study, all examinations were performed by one examiner (H.T.) with great experience of intrauterine sonography, which reduced intra-observer variability. Consequently, a low coefficient of variation for brain vesicle measurements (<10%) was obtained. Reduced reproducibility of measuring small embryonic structures and/or large biological variation of parameters results in reduced values of r2 (Blaas et al., 1995b). However, high r2 values for embryonic brain vesicle measurements were obtained in this study.
With respect to the comparison of embryonic brain vesicle measurements between previous transvaginal sonographic studies (Blaas et al., 1994, 1995a) and our intrauterine sonographic investigation, there are a few subtle differences. In transvaginal sonographic study, the length of telencephalon was gradually increasing between 7 and 9 weeks (Blaas et al., 1994), whereas this parameter was almost constant over the same period in our study. Surprisingly, the width of diencephalon decreased slowly between 7 and 9 weeks in the transvaginal sonographic study (Blaas et al., 1994). However, the width of diencephalon moderately increased during the early first trimester of pregnancy in this study. The cause of these discrepancies of embryonic brain vesicle measurements between previous transvaginal sonographic studies and ours is currently unknown. One possible explanation is that finer image quality of very small embryonic brain structures could not be obtained using transvaginal sonography, even if using a 7.5 MHz transvaginal probe, so the problem of image quality in the transvaginal approach may make the measurements of embryonic brain vesicles less reliable during this period.
With respect to the planes and sections used to locate embryonic brain anatomical landmarks in this study, the same methods were employed to obtain embryonic brain measurements as those employed in transvaginal sonography (Blaas et al., 1994, 1995a). Timor-Tritsch and Monteagudo (1996) proposed standardized transvaginal neurosonographic images of the fetal brain and a new nomenclature that more closely reflects the true anatomical sections (Timor-Tritsch and Monteagudo, 1996). However, fetal ages of their study group ranged from 18–40 weeks of gestation, whereas our embryonic ages varied from 7–9.9 weeks gestation. Therefore, the new nomenclature proposed by Timor-Tritsch and Monteagudo (1996) may not be suitable for embryonic brain anatomical landmarks.
Blaas et al. (1995c) reported that ultrasound technology used in their study has reached a stage where structures of only a few millimeters can be imaged in vivo in three dimensions with a quality that resembles the plaster figures used in embryonic laboratories (Blaas et al., 1995c). Nevertheless, their three-dimensional sonographic embryonic brain images were not so fine because they used a 7.5 MHz transvaginal probe, highlighting the problem of image quality in the transvaginal approach. If intrauterine sonography with a 20 MHz high-resolution transducer is used for three- dimensional sonographic embryonic brain structures, it will be possible to obtain finer image quality of small embryonic brain cavities.
With respect to limitations associated with intrauterine sonography, it is an invasive diagnostic procedure requiring sterile conditions. Its safety has not been established. Although we and previous authors (Ragavendra et al., 1991, 1993; Fujiwaki et al., 1995; Hata et al., 1996) encountered no immediate complications, the use of intrauterine sonography is not recommended for routine clinical examination in pregnancy at present. Prospective further study is needed to clarify the safety of intrauterine sonography for its clinical use in the early first trimester of pregnancy.
In conclusion, intrauterine sonography provides a novel means for precise measurement of brain vesicles of the embryo. These results suggest that intrauterine sonography may become an important modality in future embryological research and in detection of embryonic brain abnormalities in the early first-trimester pregnancy.
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Acknowledgments |
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This study was supported by Health Sciences Research Grants for Specific Diseases `Intractable Hydrocephalus' (1999-SD-17) from the Ministry of Health and Welfare, Japan.
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Notes |
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1 To whom correspondence should be addressed.E-mail: hiroka{at}kms.ac.jp
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Submitted on November 15, 1999; accepted on March 7, 2000.
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