Original Article
47
Novel Insights into Early Embryonic Demise via 3D Surface Rendered Imaging in 107 Cases
Authors
D. R. Hartge, A. Schröer, J. Weichert
Affiliation
Prenatal Medicine, University Hospital of Schleswig-Holstein, Luebeck
Key words
Abstract
Zusammenfassung
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Purpose: Sonographic imaging techniques including 3 D volumetry were evaluated in women with missed abortion. Special emphasis was put on the impact of additional information regarding the etiology of the demise and improved visualization of embryonic and fetal anomalies due to the application of the latest imaging tools, e. g. HD live™. Parental acceptance of a more realistic display of the embryo/fetus in missed abortion was analyzed. Materials and Methods: Between 09/2009 and 09/ 2012, 107 pregnancies with a missed abortion in the first trimester were included in this prospective survey. Using a transvaginal approach, all 2 D and 3 D studies were carried out with high-resolution 5 – 9 and 6 – 12 MHz probes. Results: The mean gestational age was 70.3 days (49 – 110 days). The difference between estimated gestational age and sonographic age at evaluation for missed abortion was 13.5 days (–13 – 40 days). Additional information via three-dimensional volume acquisition, like craniofacial deformities, clefts, neural tube defects, abdominal wall defects and caudal regression syndrome, could be documented in 23/107 cases (21.5 %). In 2/107 cases the parents disapproved of the 3 D visualization due to the more realistic presentation. Conclusion: 3 D ultrasound in cases of missed abortion can provide additional information regarding the presence of structural anomalies. It may give further details regarding the timing of embryonic/fetal demise in early pregnancy. Sufficient informational value is regularly obtained in cases having a CRL > 8 mm. In counseling parents, 3 D ultrasound is a useful tool and is generally well accepted.
Ziel: Das Ziel dieser Untersuchung war zu prüfen, welchen Stellenwert die Qualitätsverbesserung der dreidimensionalen sonografischen Bildgebung von embryonalen und fetalen Oberflächenstrukturen bei verhaltenen Aborten im ersten Trimenon hat und welche zusätzlichen Informationen durch die Anwendung neuester Techniken zur Oberflächendarstellung, z. B. HDliveTM, bezüglich der Ursache der verhaltenen Aborte gewonnen werden können. Zusätzlich wurde die Akzeptanz dieser realistischeren Darstellung des Embryos und Feten bei verhaltenem Abort bei den betroffenen Eltern ausgewertet. Material und Methoden: Zwischen 09/2009 und 09/2012 wurden insgesamt 107 Schwangerschaften mit einem verhaltenen Abort in diese prospektive Untersuchung eingeschlossen. Die sonografische, transvaginale 2-D- und 3-D-Evaluierung erfolgte über hochauflösende 5 – 9 und 6 – 12 MHz Ultraschallsonden. Ergebnisse: Das durchschnittliche Schwangerschaftsalter betrug 70,3 Tage (49 – 110 Tage). Die Differenz zwischen geschätztem und sonografischem Gestationsalter bei Eintritt des embryonalen und fetalen Ablebens betrug 13,5 Tage (–13 – 40 Tage). Durch die zusätzliche 3-D-Sonografie ließen sich kranio-faziale Deformitäten und Spaltbildungen, Neuralrohr- und Bauchwanddefekte, sowie ein kaudales Regressionssyndrom in 23/107 (21,5 %) Fällen nachweisen. Bei 2/107 Fällen lehnten die Eltern die 3-D-Sonografie wegen der realistischeren Darstellung ab. Schlussfolgerung: Die Hinzunahme der dreidimensionalen Ultrasonographie kann wertvolle Zusatzinformationen bei Fehlbildungen von Embryonen und Feten bei verhaltenem Abort liefern. Sie kann zudem Hinweise zum Zeitpunkt des Eintritts des verhaltenen Abortes in der Frühschwangerschaft geben. Die ausreichende Darstellbarkeit von embryonalen Strukturen scheint ab einer SSL
● ultrasound 3 D/4 D ● malformation ● chromosomal aberration ● abortion " " "
received accepted
18.12.2012 8.7.2013
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1350327 Published online: January 13, 2014 Ultraschall in Med 2015; 36: 47–53 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0172-4614
Correspondence Dr. David Rafael Hartge Prenatal Medicine, University Hospital of Schleswig-Holstein Ratzburger Allee 160 23538 Luebeck Germany Tel.: 00 49 45 15 00 21 49 Fax: 00 49 45 15 00 21 96 [email protected]
Hartge DR et al. Novel Insights into … Ultraschall in Med 2015; 36: 47–53
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Neue Aspekte bei der dreidimensionalen, oberflächenbearbeiteten Darstellung von 107 Embryonen und Feten bei verhaltenem Abort
Original Article
von über 8 mm gegeben zu sein. Bei der Beratung der betroffenen Eltern hat sich der 3-D-Ultraschall als sinnvolle Maßnahme bewährt.
Purpose !
Spontaneous abortion may be defined as pregnancy loss prior to the completed 20th week of gestation [1]. It comprises different clinical entities including threatened abortion, inevitable abortion, incomplete abortion, complete abortion and missed abortion. Serial hCG-testing of maternal urine samples from women with normal fertility revealed an early pregnancy failure after implantation of 31 %. Approximately two-thirds of these abortions were exclusively detected via positive hCG-level results [2]. Spontaneous abortion is likely to occur in 10 – 20 % of clinically recognized pregnancies [2, 3]. In roughly one-fifth of cases, fetal anomalies can be detected during pathological examination [4]. Ultrasound examination is considered to be the gold standard for the evaluation of early embryonic and fetal demise [5]. Standard 2 D sonographic evaluation is not always capable of giving satisfactory information regarding the putative underlying etiology of the embryonic and fetal demise. An additional tool to improve the informational value of an ultrasound interrogation at this time of pregnancy is the use of modern 3 D and 4 D techniques, as they provide valuable data with respect to the surface and morphology of the entire embryo and fetus thus facilitating diagnostic attempts to elucidate the possible etiology of the early demise [6 – 9]. In this study we focused on the diagnostic informational value of new ultrasound techniques including 3 D volumetry, 4 D imaging and post-rendering process of actual and stored volume sets by the application of HD liveTM technology. Additionally, we analyzed parental acceptance of a more realistic display of the embryo/fetus in missed abortion.
Materials and Methods !
This prospective study was conducted between September 2009 and September 2012 and included 118 asymptomatic pregnant women diagnosed with a missed abortion in the first trimester of gestation. All patients were referred to our unit by local obstetricians for dilatation and curettage (D&C). At our unit a transvaginal scan was carried out by two physicians with expertise in fetal ultrasound according to national and international guidelines using high-resolution 6 – 12 MHz curved array probes. The equipment used consisted of Voluson 730 Expert and E8 Expert ultrasound machines (GE Healthcare, Milwaukee, Wisconsin, USA). The examination included 2 D and 3 D surveys with a post-rendering process of actual and stored volume sets and application of HDliveTM technology (HDliveTM had been routinely used since November 2011). 3 D static imaging was carried out in a standardized manner with a sector width of 35° and a sweep speed of 2 – 3 seconds (quality high). To enhance the image quality, harmonic imaging remained enabled during the examination as well as all pre-processing mechanisms. Cases in which the embryonic axis could not be determined or cases with advanced autolysis visualization were defined as poor. The embryos were classified based on the Carnegie stages [10]. Nine cases (7.6 %) in which an embryo could not be detected had to be excluded from the final analysis. Two (1.7 %) women opted for termination of the pregnancy at another institution without
Hartge DR et al. Novel Insights into … Ultraschall in Med 2015; 36: 47–53
subsequent pathologic/genetic examination and were therefore " Fig. 1). also excluded from the final analysis (● Pregnancy demise due to standard 2 D features – including embryonic crown-rump length (CRL) above 5 mm without cardiac activity or CRL below 5 mm without embryonic growth at an interval of not less than 7 days [11] – were confirmed in all remaining 107/107 (100 %) cases. In all cases D&C lead to embryonic and fetal remnants that were unsuitable for postpartal macroscopic evaluation. Therefore, intact embryonic or fetal corpora could neither be preserved nor brought to pathological examination. For all women the complete medical history including body-mass index (BMI), comorbidities, current medication, prior surgery, allergies and previous pregnancies was documented. All women enrolled in this study gave their informed consent to participate in this survey. According to national health guidelines, embryonic/fetal karyotyping was only performed in women with repeated miscarriages. Where karyotype was available it was incorporated in this study.
Results !
A total of 107 cases of missed abortion in the first trimester were " Fig. 1). The mean maternal age was 32.4 years (16 – analyzed (● 46 years). One-third (37/107, 34.6 %) of the pregnant women were 35 years of age or older. Thirty-nine (36.5 %) women were primiparae, 46/107 (43.0 %) had delivered at least one healthy child prior to this episode of missed abortion, 34/107 (31.8 %) had had 1 or 2 abortions and 7/107 (6.5 %) had already had 3 or more abortions (= recurrent pregnancy loss, RPL). The mean maternal BMI at diagnosis was 23.8 (15.6 – 41.9). In 16/107 (15.0 %) cases, fetal karyotype was available. 11/16 showed normal chromosomal distribution (female n = 7, male n = 4), 5/16 had an altered karyotype: 47XX+ 9 n = 1; 47XX+ 16 n = 2; 47XX+ 18 n = 1, 47XY+ 22 n = 1. Histopathological examination of placental tissue was performed in 98/107 (91.6 %) and showed features of choriovillous maldevelopment probably in conjunction with chromosomal anomalies in the embryo and fetus in 37/98 (37.8 %). The mean gestational age (based on the first day of the last menstruation) at the time of diagnosis was 70.3 days (49 – 110 days). The mean difference between the calculated gestational age and the gestational age assessed by crown-rump length (CRL) at diagnosis was ΔGA = 13.5 days (–13 – 40 days). There were 92/107 (86.0 %) singleton pregnancies, 4/15 monochorionic-diamniotic twin pregnancies, 5/15 dichorionic-diamniotic twin pregnancies, 2/15 dichorionic-triamniotic triplet pregnancies, 1/15 trichorionic-triamniotic triplet pregnancy, 2/ 15 tetrachorionic-tetraamniotic quadruplet pregnancies and 1/ 15 twin pregnancy with unspecified chorionicity. Maternal features included 3/107 (2.8 %) cases in which the selective estrogen receptor modulator clomifene had been used for the stimulation of ovulation in patients with polycystic ovary syndrome. In 2 cases this stimulation resulted in a quadruplet pregnancy and in 1 case in a singleton pregnancy. There were 3/ 107 (2.8 %) cases of in-vitro fertilization due to paternal sub-fertility which all resulted in a singleton pregnancy. In 4/107 (3.7 %)
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Original Article
49
Fig. 1 Sonographic evaluation and distribution of prenatally detected anomalies in 107 cases of missed abortion.
Referred women with suspected missed abortion in first trimester n=118
Missed inclusion criteria n=11/118 (9.3%)
Abb. 1 Sonografische Befunde und Verteilung der pränatal detektierten Fehlbildungen in 107 Fällen eines verhaltenen Abortes.
- no embryo detectable n=9 - lost to follow-up
n=2
Prenatal sonographic confirmation of missed abortion n=107
Prenatal sonographic evaluation feasible
Good embryonic/fetal visualization
L imited embryonic/fetal visualization
n=61/107 (57.0%)
n=46/107 (43.0%)
Detected anomalies n=25 - enlarged yolk sac
n=17
- small/missing yolk sac
n=6
- hydrops fetalis
n=2
Detected anomalies n=43/61 Anomalies detected by conventional 2D ultrasound n=21/43 - enlarged yolk sac
n=11
- hydrops fetalis
n=5
- small/missing yolk sac
n=4
- umbilical hernia
n=3
- prominent cervical flexure
n=3
- hygroma colli
n=2
- gastroschisis
n=1
- umbilical cyst
n=1
Anomalies detected by 3D/4D ultrasound only n=23/43 - disproportional growth
n=7
- anomalous shaping of the head
n=6
- facial cleft
n=5
- neural tube defect
n=2
- caudal regression
n=1
- micrognathia
n=1
- nuchal cord
n=1
of the cases, the women needed medical supplementation of levothyroxine due to apparent hypothyroidism. One of the gravida suffered from hyperhomocysteinemia. She added vitamin B6, B12, and folic acid to her daily diet. Another 3/107 women reported a daily intake of 100 mg aspirin due to a factor XII-deficiency, an idiopathic thrombocytosis and a cerebral insult without residues of unknown etiology, respectively. Another woman had known
von Willebrand disease without the need for treatment and a second gravida had a known factor V Leiden mutation without current heparin treatment. Sonographic visualization of the embryo and fetus was classified as limited in 46/107 (43.0 %) cases. The mean CRL in these cases was 10.3 mm (2.8 – 49.9 mm), the mean discrepancy between the estimated gestational age and the gestational age based on
Hartge DR et al. Novel Insights into … Ultraschall in Med 2015; 36: 47–53
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n=107/107 (100%)
Original Article
the measurement of the CRL at the time of diagnosis was 16.0 days (–13 – 39 days). The mean CRL in embryos and fetuses with good visualization was 22.0 mm (8.5 – 55.6 mm). The mean interval of the estimated gestational age and the gestational age at diagnosis was 13.3 days (–1 – 40 days).
In 43/61 cases with good visualization, a variety of structural anomalies could be detected. In 21 of these cases, the following abnormalities were detectable by conventional 2 D ultrasound " Fig. 2); hydrops fetalis examination: enlarged yolk sac n = 11 (● n = 5; small/missing yolk sac = 4; umbilical hernia n = 3 " Fig. 3c); prominent cervical flexure n = 3 ( " Fig. 4a); hygroma (● ● " Fig. 3b); umbilical cyst n = 1 colli n = 2; fetal gastroschisis n = 1 (● " Fig. 3a). The remaining 2¾3 anomalies were detectable solely (● by using 3 D/4 D volume ultrasound: disproportional growth " Fig. 6a, b); cranion = 7; anomalous shaping of the head n = 6 (● " Fig. 5a, b); neural tube defect n = 2 ( " Fig. 4b); facial cleft n = 5 (● ● caudal regression syndrome n = 1; micrognathia n = 1; nuchal " Fig. 1 and " Table 1, oncord n = 1 (for a detailed overview see ● ● line). All women enrolled in this study appreciated the reconfirmation of the embryonic or fetal demise during the additional examination. Even though this meant repeated visual confrontation of the end of the pregnancy, it was considered to be helpful for accepting the situation in all cases, not only in those where altered embryos or fetuses were found. In 28/107 women, HDlive was used during the ultrasound scan. The representation of this imaging mode was also appreciated by most of the women. 2 women, however, stated that this sonographic depiction was too realistic and that they would prefer a less realistic display in obstetric ultrasound in the future. In 73/107 (68.2 %) cases, the examination included the use of an E8 Expert ultrasound machine and the stored volumes were processed with HDliveTM offline.
Conclusion Fig. 2 HDlive™ sonographic image of an embryo in missed abortion with a CRL of 20.0 mm surrounded by the amniotic sheet; umbilical cord incision to the left and an enlarged yolk sac to the right of the embryo. Abb. 2 HDlive™ Utraschallbild eines Embryo eines verhaltenen Abortes mit einer Scheitel-Steiß-Länge (SSL) von 20,0 mm umgeben von der Amnionhülle; Nabelschnuransatz auf der linken Seite und vergrößerter Dottersack auf der rechten Seite des Embryo darstellbar.
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Missed abortion is the most common diagnosis in early pregnancy loss [12, 13]. Women experiencing a miscarriage suffer from long-term psychological stress and may even exceed grief scores demonstrated in people with the loss of a close relative [14]. A follow-up visit in early fetal demise and a diagnosis leading to a possible explanation for a missed abortion may be helpful for
Fig. 3 HDlive™ sonographic images of embryos in missed abortion: a with an umbilical cord cyst (CRL of 19.5 mm) (white arrow), b with a gastroschisis (CRL of 29.5 mm) (black arrows), c with an umbilical hernia (CRL of 28.5 mm) (white arrow). Abb. 3 HDlive™ Ultraschallbilder von Embryonen eines verhaltenen Abortes: a mit einer Nabelschnurzyste (SSL 19,5 mm) (weisser Pfeil), b mit einer Gastroschisis (SSL 29,5 mm) (schwarze Pfeile), c mit einer Umbilicalhernie (SSL 28,5 mm) (weisser Pfeil).
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Original Article
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Fig. 4 HDlive™ sonographic images of embryos in missed abortion: a with a prominent cervical flexure (CRL of 17.6 mm) (white arrows), b with an occipito-nuchal neural tube defect (38.9 mm) (white arrow)
Fig. 5 HDlive™ sonographic images of embryos in missed abortion: a with a double lateral cleft (CRL of 18.9 mm) (white arrows), b with a median facial cleft (CRL of 20.9 mm) (white arrow) Abb. 5 HDlive™ Ultraschallbilder von Embryonen eines verhaltenen Abortes: a mit einer beidseitigen Mittelgesichtspalte (SSL 18,9 mm) (weisse Pfeile), b mit einer medianen Mittelgesichtspalte (SSL 20,9 mm) (weisser Pfeil)
Fig. 6 HDlive™ sonographic images of embryos: a with disproportional, elongated head (CRL of 19.8 mm), b with disproportional, elongated head (CRL of 16.1 mm) Abb. 6 HDlive™ Ultraschallbilder von Embryonen eines verhaltenen Abortes: a mit disproportionierter, elongierter Kopfregion (SSL 19,8 mm), b mit mit disproportionierter, elongierter Kopfregion (SSL 16,1 mm)
the affected women in coping with the present situation [10, 15]. Therefore, an analysis of alterations which may be found and what conclusions can be drawn from ultrasound interrogation are important issues also in counseling such patients and was
consistently appreciated by the women participating in our study. The average gestational age at which embryonic demise was likely to take place in our study was 56 days (8 + 0 gestational weeks).
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Abb. 4 HDlive™ Ultraschallbilder von Embryonen eines verhaltenen Abortes: a mit einer prominenten Nackenflexur (SSL 17,6 mm) (weisse Pfeile), b mit einem okzipito-nuchalen Neuralrohrdefekt (SSL 38,9 mm) (weisser Pfeil)
Original Article
This is in accordance with data from previous studies [10, 16]. 3 D visualization of a vital embryo at 8 weeks has been shown to be feasible [17]. The reason for early pregnancy loss may be aneuploidies in up to 50 % of cases [18]. In our study we could detect chromosomal anomalies in 5 cases and in an additional 32 cases placental evaluation could not rule out the possible occurrence of a chromosomal anomaly. In summary, 37/98 (37.8 %) cases in our series were or may have been affected by a chromosomal anomaly. Eleven (10.3 %) women presented with a missed abortion without detectable risk factors or proven or suspected fetal alteration. Sonographic transvaginal measurement of CRL in the early stages of pregnancy is proven to be a reliable technique [19]. In our study the mean CRL in embryos and fetuses where good visualization was achieved was 22.0 mm, ranging from 8.5 – 55.6 mm. The other group with considerable loss of image clarity showed a mean CRL of 10.3 mm (2.8 – 49.9 mm). Thirty-one of forty-six cases with limited sonographic visualization presented with a CRL below 8 mm. 15/46 cases had a CRL above 8 mm but sufficient sonographic visualization was not feasible due to failure to determine an embryonic axis and/or due to advanced autolysis or unfavorable maternal conditions. In the group with good visualization, none of the embryos was smaller than 8.5 mm. Sufficient visualization and therefore adequate evaluation of the embryos and fetuses in our study seem to be size-dependent with a minimum CRL of 8 mm. As a result of the cessation of the embryonic/fetal heartbeat, 2 D sonographic presentability of the inner organs and their margins is considered to be impossible due to increasing tissue homogeneity. On the other hand, 3 D surface evaluation is possible in embryonic death and allows a direct and meaningful assessment and comparison with embryos showing normal development [6, 20, 21]. Results from those studies may have a valuable impact on our knowledge of the possible reasons for early pregnancy loss. In our study we were able to show several embryonic and fetal alterations often related to a missed abortion. Increased yolk sac diameter, as shown in our data, is not an uncommon finding in missed abortions, as it is reportedly detectable in about one-fifth of such cases [22]. The yolk sac is the primary hemopoetic organ and may reflect deficits in involved mechanisms in embryos with trisomy 21, whereas trisomy 13 and 18 seem not to present with markedly enlarged yolk sac dimensions in sonographic assessment [21, 23]. Cranio-facial clefts can be detected from the 8th embryonic week onwards. In our study 5 cases with clefts could be detected. Cleft palates could not have been evaluated due to insufficient image clarity of inner embryonic structures. The occurrence of clefts (cleft lip/palate) is potentially associated with trisomies but also rubella infection, maternal medication (e. g. valproic acid, phenytoin), maternal alcohol intake, cigarette smoking and folic acid deficiency as well as a variety of different syndromes. An exact allocation of the underlying cause of the clefts could not be achieved in our study. Seven embryos and fetuses showed markedly disproportional growth with underrepresented body and limbs and a relatively enlarged but normally shaped head. This was considered to be an early and severe presentation of an asymmetric type of impaired intrauterine growth with a strong association with trisomy 13, trisomy 18 and triploidy as a putative underlying cause of the missed abortion. Hydrops fetalis was seen in another 5 cases. The literature describes a broad variety of conditions provoking hydrops fetalis in-
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cluding aneuploidies, infections, cardiovascular alterations, immunological hydrops, twin-to-twin transfusion syndrome in multiple pregnancies and maternal impairments like severe anemia and severe diabetes mellitus. Whether the cases of hydrops fetalis in our study are secondary to associated problems probably responsible for the demise of the embryo and fetus or if these hydropic alterations are due to advanced autolyses is impossible to say at this point. In three cases a prominent cervical flexure was present at the nuchal area of the embryo. As reported previously [6], an abnormally marked flexure at the level of the hindbrain of embryos can be seen in cases of missed abortion in the first trimester of pregnancy, but the clinical impact of this sign has not yet been clarified. In one case micrognathia was detected. Chromosomal testing revealed trisomy 18 of the embryo in question. There was one case showing caudal regression with a tail-like lower pole and no limb buds. An insufficient supply of folic acid may cause caudal regression syndrome as shown in our case. The correct diagnosis of caudal regression syndrome may be optimally achieved by a 3 D ultrasound interrogation [24]. In three embryos an umbilical hernia defined as a physiological midgut herniation was diagnosed during examination. During embryonic development there is eventration of the intestines which is a normal phenomenon in regular embryonic growth and is typically without pathological value. With the beginning of the 12th week of gestation, umbilical hernias are normally no longer detectable. If they remain, omphaloceles may be a marker of trisomy 21, 13 and 18 in about half of the cases [24]. Hystero-embryoscopy prior to D&C for obtaining biopsies of chorionic and/or embryonic material in missed abortions may be a useful and reliable tool for karyotyping the embryo and fetus [25, 26]. Hystero-embryoscopy can provide similar results regarding the visualization of failed pregnancy in early gestation. This invasive method of direct demonstration of embryonic specimen cannot produce satisfying images in all cases. Despite the higher costs, it has a failure rate above 10 %. In terms of the detection of external embryonic and fetal anomalies, modern hysteroembryoscopy and transvaginal ultrasound may be seen as equally capable of producing significant images [27]. If no direct biopsy of chorionic or embryonic tissue is needed, additional hysteroembryoscopy should be deliberated as it may have no new impact on diagnoses of external, surface-related abnormalities in early pregnancy. We conclude that the visualization of embryonic and fetal structures in the early first trimester of pregnancy in missed abortions is negatively influenced by a small size of the target. It may be complicated by advanced autolysis and anomalies altering the shape of the entire body like hydrops fetalis. Transvaginal ultrasound in cases of missed abortion – and threedimensional volume acquisition in particular – has been shown to be a reliable and feasible technique which contributes valuable information regarding the possible underlying cause of early embryonic and fetal demise. This noninvasive and efficient examination performed by experienced physicians is widely appreciated by the affected gravida and can easily be added to daily practice. Three-dimensional transvaginal ultrasound should therefore be implemented as an examination routinely offered to women with a missed abortion.
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Original Article
47
Novel Insights into Early Embryonic Demise via 3D Surface Rendered Imaging in 107 Cases
Authors
D. R. Hartge, A. Schröer, J. Weichert
Affiliation
Prenatal Medicine, University Hospital of Schleswig-Holstein, Luebeck
Key words
Abstract
Zusammenfassung
"
!
!
Purpose: Sonographic imaging techniques including 3 D volumetry were evaluated in women with missed abortion. Special emphasis was put on the impact of additional information regarding the etiology of the demise and improved visualization of embryonic and fetal anomalies due to the application of the latest imaging tools, e. g. HD live™. Parental acceptance of a more realistic display of the embryo/fetus in missed abortion was analyzed. Materials and Methods: Between 09/2009 and 09/ 2012, 107 pregnancies with a missed abortion in the first trimester were included in this prospective survey. Using a transvaginal approach, all 2 D and 3 D studies were carried out with high-resolution 5 – 9 and 6 – 12 MHz probes. Results: The mean gestational age was 70.3 days (49 – 110 days). The difference between estimated gestational age and sonographic age at evaluation for missed abortion was 13.5 days (–13 – 40 days). Additional information via three-dimensional volume acquisition, like craniofacial deformities, clefts, neural tube defects, abdominal wall defects and caudal regression syndrome, could be documented in 23/107 cases (21.5 %). In 2/107 cases the parents disapproved of the 3 D visualization due to the more realistic presentation. Conclusion: 3 D ultrasound in cases of missed abortion can provide additional information regarding the presence of structural anomalies. It may give further details regarding the timing of embryonic/fetal demise in early pregnancy. Sufficient informational value is regularly obtained in cases having a CRL > 8 mm. In counseling parents, 3 D ultrasound is a useful tool and is generally well accepted.
Ziel: Das Ziel dieser Untersuchung war zu prüfen, welchen Stellenwert die Qualitätsverbesserung der dreidimensionalen sonografischen Bildgebung von embryonalen und fetalen Oberflächenstrukturen bei verhaltenen Aborten im ersten Trimenon hat und welche zusätzlichen Informationen durch die Anwendung neuester Techniken zur Oberflächendarstellung, z. B. HDliveTM, bezüglich der Ursache der verhaltenen Aborte gewonnen werden können. Zusätzlich wurde die Akzeptanz dieser realistischeren Darstellung des Embryos und Feten bei verhaltenem Abort bei den betroffenen Eltern ausgewertet. Material und Methoden: Zwischen 09/2009 und 09/2012 wurden insgesamt 107 Schwangerschaften mit einem verhaltenen Abort in diese prospektive Untersuchung eingeschlossen. Die sonografische, transvaginale 2-D- und 3-D-Evaluierung erfolgte über hochauflösende 5 – 9 und 6 – 12 MHz Ultraschallsonden. Ergebnisse: Das durchschnittliche Schwangerschaftsalter betrug 70,3 Tage (49 – 110 Tage). Die Differenz zwischen geschätztem und sonografischem Gestationsalter bei Eintritt des embryonalen und fetalen Ablebens betrug 13,5 Tage (–13 – 40 Tage). Durch die zusätzliche 3-D-Sonografie ließen sich kranio-faziale Deformitäten und Spaltbildungen, Neuralrohr- und Bauchwanddefekte, sowie ein kaudales Regressionssyndrom in 23/107 (21,5 %) Fällen nachweisen. Bei 2/107 Fällen lehnten die Eltern die 3-D-Sonografie wegen der realistischeren Darstellung ab. Schlussfolgerung: Die Hinzunahme der dreidimensionalen Ultrasonographie kann wertvolle Zusatzinformationen bei Fehlbildungen von Embryonen und Feten bei verhaltenem Abort liefern. Sie kann zudem Hinweise zum Zeitpunkt des Eintritts des verhaltenen Abortes in der Frühschwangerschaft geben. Die ausreichende Darstellbarkeit von embryonalen Strukturen scheint ab einer SSL
● ultrasound 3 D/4 D ● malformation ● chromosomal aberration ● abortion " " "
received accepted
18.12.2012 8.7.2013
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1350327 Published online: January 13, 2014 Ultraschall in Med 2015; 36: 47–53 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0172-4614
Correspondence Dr. David Rafael Hartge Prenatal Medicine, University Hospital of Schleswig-Holstein Ratzburger Allee 160 23538 Luebeck Germany Tel.: 00 49 45 15 00 21 49 Fax: 00 49 45 15 00 21 96 [email protected]
Hartge DR et al. Novel Insights into … Ultraschall in Med 2015; 36: 47–53
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Neue Aspekte bei der dreidimensionalen, oberflächenbearbeiteten Darstellung von 107 Embryonen und Feten bei verhaltenem Abort
Original Article
von über 8 mm gegeben zu sein. Bei der Beratung der betroffenen Eltern hat sich der 3-D-Ultraschall als sinnvolle Maßnahme bewährt.
Purpose !
Spontaneous abortion may be defined as pregnancy loss prior to the completed 20th week of gestation [1]. It comprises different clinical entities including threatened abortion, inevitable abortion, incomplete abortion, complete abortion and missed abortion. Serial hCG-testing of maternal urine samples from women with normal fertility revealed an early pregnancy failure after implantation of 31 %. Approximately two-thirds of these abortions were exclusively detected via positive hCG-level results [2]. Spontaneous abortion is likely to occur in 10 – 20 % of clinically recognized pregnancies [2, 3]. In roughly one-fifth of cases, fetal anomalies can be detected during pathological examination [4]. Ultrasound examination is considered to be the gold standard for the evaluation of early embryonic and fetal demise [5]. Standard 2 D sonographic evaluation is not always capable of giving satisfactory information regarding the putative underlying etiology of the embryonic and fetal demise. An additional tool to improve the informational value of an ultrasound interrogation at this time of pregnancy is the use of modern 3 D and 4 D techniques, as they provide valuable data with respect to the surface and morphology of the entire embryo and fetus thus facilitating diagnostic attempts to elucidate the possible etiology of the early demise [6 – 9]. In this study we focused on the diagnostic informational value of new ultrasound techniques including 3 D volumetry, 4 D imaging and post-rendering process of actual and stored volume sets by the application of HD liveTM technology. Additionally, we analyzed parental acceptance of a more realistic display of the embryo/fetus in missed abortion.
Materials and Methods !
This prospective study was conducted between September 2009 and September 2012 and included 118 asymptomatic pregnant women diagnosed with a missed abortion in the first trimester of gestation. All patients were referred to our unit by local obstetricians for dilatation and curettage (D&C). At our unit a transvaginal scan was carried out by two physicians with expertise in fetal ultrasound according to national and international guidelines using high-resolution 6 – 12 MHz curved array probes. The equipment used consisted of Voluson 730 Expert and E8 Expert ultrasound machines (GE Healthcare, Milwaukee, Wisconsin, USA). The examination included 2 D and 3 D surveys with a post-rendering process of actual and stored volume sets and application of HDliveTM technology (HDliveTM had been routinely used since November 2011). 3 D static imaging was carried out in a standardized manner with a sector width of 35° and a sweep speed of 2 – 3 seconds (quality high). To enhance the image quality, harmonic imaging remained enabled during the examination as well as all pre-processing mechanisms. Cases in which the embryonic axis could not be determined or cases with advanced autolysis visualization were defined as poor. The embryos were classified based on the Carnegie stages [10]. Nine cases (7.6 %) in which an embryo could not be detected had to be excluded from the final analysis. Two (1.7 %) women opted for termination of the pregnancy at another institution without
Hartge DR et al. Novel Insights into … Ultraschall in Med 2015; 36: 47–53
subsequent pathologic/genetic examination and were therefore " Fig. 1). also excluded from the final analysis (● Pregnancy demise due to standard 2 D features – including embryonic crown-rump length (CRL) above 5 mm without cardiac activity or CRL below 5 mm without embryonic growth at an interval of not less than 7 days [11] – were confirmed in all remaining 107/107 (100 %) cases. In all cases D&C lead to embryonic and fetal remnants that were unsuitable for postpartal macroscopic evaluation. Therefore, intact embryonic or fetal corpora could neither be preserved nor brought to pathological examination. For all women the complete medical history including body-mass index (BMI), comorbidities, current medication, prior surgery, allergies and previous pregnancies was documented. All women enrolled in this study gave their informed consent to participate in this survey. According to national health guidelines, embryonic/fetal karyotyping was only performed in women with repeated miscarriages. Where karyotype was available it was incorporated in this study.
Results !
A total of 107 cases of missed abortion in the first trimester were " Fig. 1). The mean maternal age was 32.4 years (16 – analyzed (● 46 years). One-third (37/107, 34.6 %) of the pregnant women were 35 years of age or older. Thirty-nine (36.5 %) women were primiparae, 46/107 (43.0 %) had delivered at least one healthy child prior to this episode of missed abortion, 34/107 (31.8 %) had had 1 or 2 abortions and 7/107 (6.5 %) had already had 3 or more abortions (= recurrent pregnancy loss, RPL). The mean maternal BMI at diagnosis was 23.8 (15.6 – 41.9). In 16/107 (15.0 %) cases, fetal karyotype was available. 11/16 showed normal chromosomal distribution (female n = 7, male n = 4), 5/16 had an altered karyotype: 47XX+ 9 n = 1; 47XX+ 16 n = 2; 47XX+ 18 n = 1, 47XY+ 22 n = 1. Histopathological examination of placental tissue was performed in 98/107 (91.6 %) and showed features of choriovillous maldevelopment probably in conjunction with chromosomal anomalies in the embryo and fetus in 37/98 (37.8 %). The mean gestational age (based on the first day of the last menstruation) at the time of diagnosis was 70.3 days (49 – 110 days). The mean difference between the calculated gestational age and the gestational age assessed by crown-rump length (CRL) at diagnosis was ΔGA = 13.5 days (–13 – 40 days). There were 92/107 (86.0 %) singleton pregnancies, 4/15 monochorionic-diamniotic twin pregnancies, 5/15 dichorionic-diamniotic twin pregnancies, 2/15 dichorionic-triamniotic triplet pregnancies, 1/15 trichorionic-triamniotic triplet pregnancy, 2/ 15 tetrachorionic-tetraamniotic quadruplet pregnancies and 1/ 15 twin pregnancy with unspecified chorionicity. Maternal features included 3/107 (2.8 %) cases in which the selective estrogen receptor modulator clomifene had been used for the stimulation of ovulation in patients with polycystic ovary syndrome. In 2 cases this stimulation resulted in a quadruplet pregnancy and in 1 case in a singleton pregnancy. There were 3/ 107 (2.8 %) cases of in-vitro fertilization due to paternal sub-fertility which all resulted in a singleton pregnancy. In 4/107 (3.7 %)
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Original Article
49
Fig. 1 Sonographic evaluation and distribution of prenatally detected anomalies in 107 cases of missed abortion.
Referred women with suspected missed abortion in first trimester n=118
Missed inclusion criteria n=11/118 (9.3%)
Abb. 1 Sonografische Befunde und Verteilung der pränatal detektierten Fehlbildungen in 107 Fällen eines verhaltenen Abortes.
- no embryo detectable n=9 - lost to follow-up
n=2
Prenatal sonographic confirmation of missed abortion n=107
Prenatal sonographic evaluation feasible
Good embryonic/fetal visualization
L imited embryonic/fetal visualization
n=61/107 (57.0%)
n=46/107 (43.0%)
Detected anomalies n=25 - enlarged yolk sac
n=17
- small/missing yolk sac
n=6
- hydrops fetalis
n=2
Detected anomalies n=43/61 Anomalies detected by conventional 2D ultrasound n=21/43 - enlarged yolk sac
n=11
- hydrops fetalis
n=5
- small/missing yolk sac
n=4
- umbilical hernia
n=3
- prominent cervical flexure
n=3
- hygroma colli
n=2
- gastroschisis
n=1
- umbilical cyst
n=1
Anomalies detected by 3D/4D ultrasound only n=23/43 - disproportional growth
n=7
- anomalous shaping of the head
n=6
- facial cleft
n=5
- neural tube defect
n=2
- caudal regression
n=1
- micrognathia
n=1
- nuchal cord
n=1
of the cases, the women needed medical supplementation of levothyroxine due to apparent hypothyroidism. One of the gravida suffered from hyperhomocysteinemia. She added vitamin B6, B12, and folic acid to her daily diet. Another 3/107 women reported a daily intake of 100 mg aspirin due to a factor XII-deficiency, an idiopathic thrombocytosis and a cerebral insult without residues of unknown etiology, respectively. Another woman had known
von Willebrand disease without the need for treatment and a second gravida had a known factor V Leiden mutation without current heparin treatment. Sonographic visualization of the embryo and fetus was classified as limited in 46/107 (43.0 %) cases. The mean CRL in these cases was 10.3 mm (2.8 – 49.9 mm), the mean discrepancy between the estimated gestational age and the gestational age based on
Hartge DR et al. Novel Insights into … Ultraschall in Med 2015; 36: 47–53
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n=107/107 (100%)
Original Article
the measurement of the CRL at the time of diagnosis was 16.0 days (–13 – 39 days). The mean CRL in embryos and fetuses with good visualization was 22.0 mm (8.5 – 55.6 mm). The mean interval of the estimated gestational age and the gestational age at diagnosis was 13.3 days (–1 – 40 days).
In 43/61 cases with good visualization, a variety of structural anomalies could be detected. In 21 of these cases, the following abnormalities were detectable by conventional 2 D ultrasound " Fig. 2); hydrops fetalis examination: enlarged yolk sac n = 11 (● n = 5; small/missing yolk sac = 4; umbilical hernia n = 3 " Fig. 3c); prominent cervical flexure n = 3 ( " Fig. 4a); hygroma (● ● " Fig. 3b); umbilical cyst n = 1 colli n = 2; fetal gastroschisis n = 1 (● " Fig. 3a). The remaining 2¾3 anomalies were detectable solely (● by using 3 D/4 D volume ultrasound: disproportional growth " Fig. 6a, b); cranion = 7; anomalous shaping of the head n = 6 (● " Fig. 5a, b); neural tube defect n = 2 ( " Fig. 4b); facial cleft n = 5 (● ● caudal regression syndrome n = 1; micrognathia n = 1; nuchal " Fig. 1 and " Table 1, oncord n = 1 (for a detailed overview see ● ● line). All women enrolled in this study appreciated the reconfirmation of the embryonic or fetal demise during the additional examination. Even though this meant repeated visual confrontation of the end of the pregnancy, it was considered to be helpful for accepting the situation in all cases, not only in those where altered embryos or fetuses were found. In 28/107 women, HDlive was used during the ultrasound scan. The representation of this imaging mode was also appreciated by most of the women. 2 women, however, stated that this sonographic depiction was too realistic and that they would prefer a less realistic display in obstetric ultrasound in the future. In 73/107 (68.2 %) cases, the examination included the use of an E8 Expert ultrasound machine and the stored volumes were processed with HDliveTM offline.
Conclusion Fig. 2 HDlive™ sonographic image of an embryo in missed abortion with a CRL of 20.0 mm surrounded by the amniotic sheet; umbilical cord incision to the left and an enlarged yolk sac to the right of the embryo. Abb. 2 HDlive™ Utraschallbild eines Embryo eines verhaltenen Abortes mit einer Scheitel-Steiß-Länge (SSL) von 20,0 mm umgeben von der Amnionhülle; Nabelschnuransatz auf der linken Seite und vergrößerter Dottersack auf der rechten Seite des Embryo darstellbar.
!
Missed abortion is the most common diagnosis in early pregnancy loss [12, 13]. Women experiencing a miscarriage suffer from long-term psychological stress and may even exceed grief scores demonstrated in people with the loss of a close relative [14]. A follow-up visit in early fetal demise and a diagnosis leading to a possible explanation for a missed abortion may be helpful for
Fig. 3 HDlive™ sonographic images of embryos in missed abortion: a with an umbilical cord cyst (CRL of 19.5 mm) (white arrow), b with a gastroschisis (CRL of 29.5 mm) (black arrows), c with an umbilical hernia (CRL of 28.5 mm) (white arrow). Abb. 3 HDlive™ Ultraschallbilder von Embryonen eines verhaltenen Abortes: a mit einer Nabelschnurzyste (SSL 19,5 mm) (weisser Pfeil), b mit einer Gastroschisis (SSL 29,5 mm) (schwarze Pfeile), c mit einer Umbilicalhernie (SSL 28,5 mm) (weisser Pfeil).
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Fig. 4 HDlive™ sonographic images of embryos in missed abortion: a with a prominent cervical flexure (CRL of 17.6 mm) (white arrows), b with an occipito-nuchal neural tube defect (38.9 mm) (white arrow)
Fig. 5 HDlive™ sonographic images of embryos in missed abortion: a with a double lateral cleft (CRL of 18.9 mm) (white arrows), b with a median facial cleft (CRL of 20.9 mm) (white arrow) Abb. 5 HDlive™ Ultraschallbilder von Embryonen eines verhaltenen Abortes: a mit einer beidseitigen Mittelgesichtspalte (SSL 18,9 mm) (weisse Pfeile), b mit einer medianen Mittelgesichtspalte (SSL 20,9 mm) (weisser Pfeil)
Fig. 6 HDlive™ sonographic images of embryos: a with disproportional, elongated head (CRL of 19.8 mm), b with disproportional, elongated head (CRL of 16.1 mm) Abb. 6 HDlive™ Ultraschallbilder von Embryonen eines verhaltenen Abortes: a mit disproportionierter, elongierter Kopfregion (SSL 19,8 mm), b mit mit disproportionierter, elongierter Kopfregion (SSL 16,1 mm)
the affected women in coping with the present situation [10, 15]. Therefore, an analysis of alterations which may be found and what conclusions can be drawn from ultrasound interrogation are important issues also in counseling such patients and was
consistently appreciated by the women participating in our study. The average gestational age at which embryonic demise was likely to take place in our study was 56 days (8 + 0 gestational weeks).
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Abb. 4 HDlive™ Ultraschallbilder von Embryonen eines verhaltenen Abortes: a mit einer prominenten Nackenflexur (SSL 17,6 mm) (weisse Pfeile), b mit einem okzipito-nuchalen Neuralrohrdefekt (SSL 38,9 mm) (weisser Pfeil)
Original Article
This is in accordance with data from previous studies [10, 16]. 3 D visualization of a vital embryo at 8 weeks has been shown to be feasible [17]. The reason for early pregnancy loss may be aneuploidies in up to 50 % of cases [18]. In our study we could detect chromosomal anomalies in 5 cases and in an additional 32 cases placental evaluation could not rule out the possible occurrence of a chromosomal anomaly. In summary, 37/98 (37.8 %) cases in our series were or may have been affected by a chromosomal anomaly. Eleven (10.3 %) women presented with a missed abortion without detectable risk factors or proven or suspected fetal alteration. Sonographic transvaginal measurement of CRL in the early stages of pregnancy is proven to be a reliable technique [19]. In our study the mean CRL in embryos and fetuses where good visualization was achieved was 22.0 mm, ranging from 8.5 – 55.6 mm. The other group with considerable loss of image clarity showed a mean CRL of 10.3 mm (2.8 – 49.9 mm). Thirty-one of forty-six cases with limited sonographic visualization presented with a CRL below 8 mm. 15/46 cases had a CRL above 8 mm but sufficient sonographic visualization was not feasible due to failure to determine an embryonic axis and/or due to advanced autolysis or unfavorable maternal conditions. In the group with good visualization, none of the embryos was smaller than 8.5 mm. Sufficient visualization and therefore adequate evaluation of the embryos and fetuses in our study seem to be size-dependent with a minimum CRL of 8 mm. As a result of the cessation of the embryonic/fetal heartbeat, 2 D sonographic presentability of the inner organs and their margins is considered to be impossible due to increasing tissue homogeneity. On the other hand, 3 D surface evaluation is possible in embryonic death and allows a direct and meaningful assessment and comparison with embryos showing normal development [6, 20, 21]. Results from those studies may have a valuable impact on our knowledge of the possible reasons for early pregnancy loss. In our study we were able to show several embryonic and fetal alterations often related to a missed abortion. Increased yolk sac diameter, as shown in our data, is not an uncommon finding in missed abortions, as it is reportedly detectable in about one-fifth of such cases [22]. The yolk sac is the primary hemopoetic organ and may reflect deficits in involved mechanisms in embryos with trisomy 21, whereas trisomy 13 and 18 seem not to present with markedly enlarged yolk sac dimensions in sonographic assessment [21, 23]. Cranio-facial clefts can be detected from the 8th embryonic week onwards. In our study 5 cases with clefts could be detected. Cleft palates could not have been evaluated due to insufficient image clarity of inner embryonic structures. The occurrence of clefts (cleft lip/palate) is potentially associated with trisomies but also rubella infection, maternal medication (e. g. valproic acid, phenytoin), maternal alcohol intake, cigarette smoking and folic acid deficiency as well as a variety of different syndromes. An exact allocation of the underlying cause of the clefts could not be achieved in our study. Seven embryos and fetuses showed markedly disproportional growth with underrepresented body and limbs and a relatively enlarged but normally shaped head. This was considered to be an early and severe presentation of an asymmetric type of impaired intrauterine growth with a strong association with trisomy 13, trisomy 18 and triploidy as a putative underlying cause of the missed abortion. Hydrops fetalis was seen in another 5 cases. The literature describes a broad variety of conditions provoking hydrops fetalis in-
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cluding aneuploidies, infections, cardiovascular alterations, immunological hydrops, twin-to-twin transfusion syndrome in multiple pregnancies and maternal impairments like severe anemia and severe diabetes mellitus. Whether the cases of hydrops fetalis in our study are secondary to associated problems probably responsible for the demise of the embryo and fetus or if these hydropic alterations are due to advanced autolyses is impossible to say at this point. In three cases a prominent cervical flexure was present at the nuchal area of the embryo. As reported previously [6], an abnormally marked flexure at the level of the hindbrain of embryos can be seen in cases of missed abortion in the first trimester of pregnancy, but the clinical impact of this sign has not yet been clarified. In one case micrognathia was detected. Chromosomal testing revealed trisomy 18 of the embryo in question. There was one case showing caudal regression with a tail-like lower pole and no limb buds. An insufficient supply of folic acid may cause caudal regression syndrome as shown in our case. The correct diagnosis of caudal regression syndrome may be optimally achieved by a 3 D ultrasound interrogation [24]. In three embryos an umbilical hernia defined as a physiological midgut herniation was diagnosed during examination. During embryonic development there is eventration of the intestines which is a normal phenomenon in regular embryonic growth and is typically without pathological value. With the beginning of the 12th week of gestation, umbilical hernias are normally no longer detectable. If they remain, omphaloceles may be a marker of trisomy 21, 13 and 18 in about half of the cases [24]. Hystero-embryoscopy prior to D&C for obtaining biopsies of chorionic and/or embryonic material in missed abortions may be a useful and reliable tool for karyotyping the embryo and fetus [25, 26]. Hystero-embryoscopy can provide similar results regarding the visualization of failed pregnancy in early gestation. This invasive method of direct demonstration of embryonic specimen cannot produce satisfying images in all cases. Despite the higher costs, it has a failure rate above 10 %. In terms of the detection of external embryonic and fetal anomalies, modern hysteroembryoscopy and transvaginal ultrasound may be seen as equally capable of producing significant images [27]. If no direct biopsy of chorionic or embryonic tissue is needed, additional hysteroembryoscopy should be deliberated as it may have no new impact on diagnoses of external, surface-related abnormalities in early pregnancy. We conclude that the visualization of embryonic and fetal structures in the early first trimester of pregnancy in missed abortions is negatively influenced by a small size of the target. It may be complicated by advanced autolysis and anomalies altering the shape of the entire body like hydrops fetalis. Transvaginal ultrasound in cases of missed abortion – and threedimensional volume acquisition in particular – has been shown to be a reliable and feasible technique which contributes valuable information regarding the possible underlying cause of early embryonic and fetal demise. This noninvasive and efficient examination performed by experienced physicians is widely appreciated by the affected gravida and can easily be added to daily practice. Three-dimensional transvaginal ultrasound should therefore be implemented as an examination routinely offered to women with a missed abortion.
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Original Article
