Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Download by: [Ahmed Kamel] Date: 19 November 2016, At: 12:41 The Journal of Maternal-Fetal & Neonatal Medicine ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20 Fetal intracranial hemorrhage: sonographic criteria and merits of prenatal diagnosis Mohamed Ali Abdelkader, Wafaa Ramadan, Amir A. Gabr, Ahmed Kamel & Rasha W. Abdelrahman To cite this article: Mohamed Ali Abdelkader, Wafaa Ramadan, Amir A. Gabr, Ahmed Kamel & Rasha W. Abdelrahman (2016): Fetal intracranial hemorrhage: sonographic criteria and merits of prenatal diagnosis, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2016.1245283 To link to this article: http://dx.doi.org/10.1080/14767058.2016.1245283 Accepted author version posted online: 09 Oct 2016. Published online: 26 Oct 2016. Submit your article to this journal Article views: 18 View related articles View Crossmark data http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–7 ! 2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.1080/14767058.2016.1245283 ORIGINAL ARTICLE Fetal intracranial hemorrhage: sonographic criteria and merits of prenatal diagnosis Mohamed Ali Abdelkader1, Wafaa Ramadan1, Amir A. Gabr1, Ahmed Kamel1, and Rasha W. Abdelrahman2 1Obstetrics and Gynecology Department, Cairo University, Cairo, Egypt and 2Radiology Department, Cairo University, Cairo, Egypt Abstract Keywords Purpose: To determine the sonographic criteria for diagnosis of fetal intracranial hemorrhage Fetal intracranial hemorrhage, fetal MRI, (ICH), using both gray scale ultrasound, and tomographic ultrasound imaging (TUI). intraventricular hemorrhage, prenatal Materials and methods: A prospective multicenter study, recruiting patients at risk of fetal ICH diagnosis, tomographic ultrasound over four years. All cases with fetal ICH had serial ultrasound assessments, including TUI, fetal imaging and postnatal MRIs. Results: Twenty-one patients were diagnosed with fetal ICH, two cases had extracerebral History (subdural) hemorrhage, 16 cases had intracerebral (intraventricular) hemorrhage and three Received 15 August 2016 cases had combined hemorrhage. The mean gestational age at which they were diagnosed was Revised 27 September 2016 29.8 ± 5.2 weeks. Seventy-six percent of cases had no identifiable risk factors. IUGR was Accepted 3 October 2016 associated with 57.9% of cases. Using grey scale ultrasound, we demonstrated clear cut Published online 21 October 2016 sonographic criteria for diagnosis of fetal ICH. TUI enabled us to detect some midline cerebral lesions not detected by grey scale 2D ultrasound alone. Fetal and postnatal MRI confirmed those findings. Conclusion: Ultrasonography can be used in the detection, classification and monitoring the progression of various types of ICH. TUI is an additional diagnostic tool that might help to detect the exact size, and extent of those lesions. Fetal MRI is not superior, but might aid in the diagnosis. Introduction Intracranial hemorrhage (ICH) is a significant problem in the low birth weight premature neonate; however it may also occur in utero [1]. Prenatal diagnosis of fetal ICH by either ultrasonography or magnetic resonance imaging (MRI) has been reported [2–4]. In most cases, the etiology of fetal ICH remains unclear but maternal trauma, thrombocytopenia, fetal coagulation disorders, severe fetal hypoxia and infections are possible predisposing factors [5]. The incidence is also unclear, mainly because of deficiencies in diagnosis, although an estimate of 1 in 10 000 pregnancies has been suggested [6]. The classification of ICH includes two major types: extracerebral (subdural hematomas) and intracerebral. Intracerebral hemorrhages are further subdivided into intra- ventricular and infratentorial (occurring within the posterior fossa) [7]. Intraventricular hemorrhages (IVH) are the most common variety of neonatal ICH, and are characteristic of the immature brain. Intraventricular hemorrhages are subdivided according to their severity into four grades: the first three Address for correspondence: Ahmed Mohamed Kamel, M.D., KasrAlainy St., P.O. Box: 11562, Garden city, Cairo, Egypt. Tel: +20 1120022332. Fax: +20 225253532. E-mail: dr.ahmed.m.kamel@gmail.com grades are limited to the ventricles, while the fourth grade includes parenchymal involvement occurring in the most severe cases [8]. Prenatal diagnosis of fetal ICH is a difficult task, as it is hard to identify, and to differentiate from other intracranial lesions. However with the continuous advancement in the field of ultrasonography, there will be an increase in the number of cases diagnosed. Awareness of diagnostic criteria, clinical significance and prognosis of this condition is necessary for informed prenatal counseling, and obstetric management. Furthermore, the recognition of prenatal brain injuries has medico-legal implications [9]. The aim of our study was to determine the sonographic criteria for the diagnosis of fetal ICH from our series of cases using both gray scale ultrasound, and tomographic ultrasound imaging (TUI), and discuss the clinical implications of in utero diagnosis of ICH. Materials and methods Study design and ethical approval This study was performed at both the feto-maternal, and fetal medicine units of Cairo university hospitals. Both units represent tertiary referral centers, as they receive over 8000 routine, or targeted prenatal ultrasonographic examinations M. A. Abdelkader et al. J Matern Fetal Neonatal Med, Early Online: 1–7 annually, from their surrounding obstetric hospitals in Cairo, and other governates in Egypt. The ethical review board approved this study at both units. Recruitment started in June 2011, and lasted till June 2015 targeting referred cases with suspected fetal ICH. An informed consent was then taken from each case, allowing detailed description for the study, permitting documentation and registration of ultrasonographic data. All evaluated cases underwent 2D ultrasound assessment, which was then enhanced using TUI technique. Fetal MRI was also done to confirm the diagnosis. All live born infants underwent postnatal evaluation by pediatric neurologists, and neonatal MRI was performed. Evaluation for possible etiology of ICH was performed in all cases including maternal history of trauma, drug exposure especially aspirin and anticoagulant therapy. Maternal and neonatal blood coagulation tests were also performed. All cases in which the diagnosis was not ICH were excluded from the study. 2D ultrasound and classifying IVH The ultrasound (US) machine used during the study period was the same at both units (voluson730; Kretz, Zipf, Austria), which was equipped with color flow imaging, pulsed Doppler, and convex probes (3.5–5 MHz) for trans-abdominal examinations, and 5–6.5 MHz for trans-vaginal examinations. All examinations were performed, and analyzed by expert sonographers with advanced training in prenatal ultrasonographic diagnosis. Central nervous system (CNS) examination included evaluation of the cavum septum pellucidum, thalamus, choroid plexus, lateral ventricles, cisterna magna and cerebellum in the transventricular, transthalamic and transcerebellar planes. We also examined the face (lips, palate, eyes, nose), spine (axial, coronal and sagittal sections), stomach, heart and great vessels, bladder, kidney, abdomen, umbilical cord insertion, and extremities to detect any associated lesions. In cases diagnosed with fetal ICH, serial examinations (ranging from 2 to 5 sonograms) were done to record the progression of the lesion(s). At each sonographic examination fetal biometry and wellbeing was performed. Also color Doppler velocimetry of fetal umbilical, and middle cerebral arteries was used if intrauterine growth retardation (IUGR) was suspected. The following parameters were assessed in cases with ICH: site, size and echogenicity of blood clots which were present either inside the ventricles, or indenting ventricular walls. Associated ventriculomegaly, hyperechogenic ventricular walls or the presence of parenchymal hyperechogenic foci suggestive of extraventricular extension were also identified. Such extension eventually ended by formation of porencephalic cyst formation, which was also reported. We used intracerebral hemorrhage as a synonym with IVH because we and other authors believe that all intracerebral hemorrhages start intraventricular [10]. If extracerebral hemorrhage (subdural hematoma) was detected; it was also reported and described. These lesions were detected as space occupying hypo echoic lesions with curved boundaries compressing the ipsilateral cerebral structures. They were Figure 1. Trans-axial view of fetal brain showing massive subdural hemorrhage, presented as a space occupying hypo echoic lesion with curved boundaries (arrow) markedly compressing the ipsilateral cerebral structures in case 15 (29 weeks). either isolated (Figure 1) or combined with IVH (Figure 2). The isolated echolucent appearance of hydrocephalic cases was excluded from the study, as well as vascular lesions with positive Doppler activity. IVH was categorized following the classification commonly used in neonates [10] with some modifications. Grade I was defined as hemorrhage limited to the germinal matrix, grade II was defined as clots filling less than 50% of the lateral ventricle with ventriculomegaly less than 15 mm at the lateral ventricular atrium, grade III was diagnosed when blood clots affected one or both lateral ventricles together with ventriculomegaly exceeding 15 mm at the lateral ventricular atrium (but with no apparent brain parenchymal injury) and grade IV included grades II–III hemorrhages accompanied by periventricular parenchymal extension which eventually ended in formation of a porencephalic cyst (Figure 3d). Ventriculomegaly was defined if the size of the atrium of the lateral ventricle exceeded 10 mm. Tomographic ultrasound imagery CNS examination was initiated with a 2D exam for better general orientation, which was then followed by 3D acquisition of the data set. This was done in the axial trans-thalamic plane with the median line perpendicular to the ultrasound beam. The quality of images which was processed at later time was dependent upon the image quality during acquisition. The image acquisition was performed using a trans- abdominal probe while adjusting for optimum local conditions (patient’s body mass index, gestational age, fetal movement and position). The multiplanar mode was used after the initial acquisition; and the volume was oriented in such a position that the central axis of the brain was horizontal in both the axial and coronal planes. When this alignment was properly realized in sagittal plane, this allowed navigation inside the acquired volume and examination of the CNS structures. Once this volume was achieved properly and stored; TUI could be used. TUI allowed realization of parallel sections in all the three axis of the acquired volume. The focus area and the distance between the sections were adjusted by the examiner in order to target the desired areas. DOI: 10.1080/14767058.2016.1245283 Prenatal ultrasound diagnosis of fetal ICH Figure 2. Trans-axial view of fetal brain showing combined ICH (IVH) and extracerebral (subdural) hemorrhage. (a) In case 17 (28 weeks), 2D grey scale ultrasound. The arrows point to both subdural hematomas and intraventricular blood clots. (b) TUI of the same case demonstrating multi-parallel cutting sections that allowed more detailed analysis of the lesions. (c) Fetal MRI confirmed the diagnosis. Note the degree of similarity and agreement between both sonographic TUI and fetal MRI. TUI demonstrates multi-parallel cutting sections that can simultaneously visualize up to eight parallel planes of section on the same screen. Hue, brightness and contrast controls were adjusted to optimize image quality. Slice width, image rotation and magnification were also done to assess the ICH or any associated lesions (Figure 2b). Fetal MRI Prenatal MRI studies (MRI, Sigma Horizon LX, GE Medical Systems, Milwaukee, WI) were performed for 19 out of 21 cases following sonographic diagnosis. A localizing gradient-echo sequence, ultra-fast T2-weighted single shot fast spin-echo (HASTE) MRI images were obtained, according to fetal position in the axial, coronal and sagittal planes with the following parameters: 1521/90/1 (TR/TE/NEX), bandwidth of 31.5 kHz, field of view of 32 . 40 cm, matrix (320 . 224), slice thickness/gap of 4/1 mm. An average of seven sequences was obtained for every examination, with mean time of 6–20 min (Figure 2c). Detailed CNS assessment was conducted including location, size and echogenic appearance of the hemorrhage, absence or presence of ventriculomegaly. Ventriculomegaly was defined if the size of the atrium of the lateral ventricle exceeds 10 mm. Repetition of some sequences was required, because the images were either degraded by fetal motion during acquisition, or because fetal motion between sequences resulted in images that are not in the true anatomic planes. Scanning time/slice was less than 1 s/image. Data was statistically described in terms of mean ± standard deviation (±SD), or frequencies (number of cases), and percentages when appropriate. All statistical calculations were done using computer program SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL) release 15 for Microsoft Windows (2006). Results Twenty-one cases of fetal ICH were diagnosed, and studied during the course of this study. This represented 21 out of 33 196 (6.3 in 10 000) cases during June 2011, and lasted till June 2015. The mean age of patients in the study was 28 ± 5.9 years, while the gestational age ranged from 19 to 38 weeks, with 29.8 ± 5.2 weeks as mean gestational age at which cases were first diagnosed. More than 76% (16/21) of the reported cases had no identifiable risk factors while in five cases; risk factors were identified, which included M. A. Abdelkader et al. J Matern Fetal Neonatal Med, Early Online: 1–7 Figure 3. Sonographic demonstration of the different grades of IVH. (a) and (b) Trans axial and para-sagittal views of fetal brain showing grade II hemorrhage in case 7 (30 weeks), with fresh blood clot appearing as a continuous echogenic cast inside the lateral ventricle (arrows). (c) Trans-axial view of grade III hemorrhage in case 11 (31 weeks) showing ventriculomegaly 415 mm with old blood clot detected inside the ventricles as a mass having complex echogenicity with an external echogenic lining, and internal hypo-echoic core (arrow). (d) Axial view of grade IV hemorrhage in case 3 (36 weeks) with large porencephalic cyst. Note the old blood clot inside the cyst (arrow). maternal trauma, preeclampsia, oral anticoagulant intake, monochorionic monoamniotic twins and history of previously affected fetus. Table 1 summarizes the ultrasound findings (both grey scale and 3D TUI), prenatal and postnatal MRI findings, associated lesions, clinical data and outcome of cases in the study. We have classified our cases of fetal ICH into three major types: . Extracerebral (subdural hematomas): two cases; . Intracerebral hemorrhages (intraventricular): 16 cases; . Combined intracerebral (intraventricular) and extracerebral hemorrhages: three cases. Concerning subdural hemorrhage, we diagnosed five cases: two cases were isolated and three cases were combined with IVH. Concerning IVH, we have diagnosed 19 cases: 16 cases were isolated and three cases were combined with subdural hemorrhage. Grade II IVH was found in 2/19 cases. Grade III IVH was found in 13/19 cases. Grade IV IVH was found in 4/19 cases. Three of the four cases of grade IV eventually developed porencephalic cyst. IVH was bilateral in 13 cases, unilateral left-sided in four cases, and right-sided in two cases. Asymmetric ventriculomegaly was reported in all bilateral cases. There were no cases with hemorrhage limited to germinal matrix (grade I in neonatal classification) but starting from grade II we have described clear cut sonographic criteria for diagnosis of fetal ICH as follows. In grade II, we found fresh blood clots inside a dilated ventricle with the ventricular atrium515 mm in diameter. Those clots appeared as intraventricular hyperechoic continuous cast-like pattern of increased echogenicity replacing the usually echo-free lateral ventricles. This represented recent hemorrhage as shown in Figures 3(a,b). In grade III IVH, which represents the old hemorrhagic phase, clots were detected inside the ventricles as a mass having complex heterogeneous echogenicity with an external echogenic lining, and an internal hypo-echoic core. The lateral ventricular atrial width exceeded 15 mm as shown in Figure 3(c). In grade IV we noticed diffuse intracerebral echogenicity adjacent to the dilated ventricles representing parenchymal extension, and in the complete liquefaction phase the ultrasound revealed in addition to criteria described in grades II and III, a cystic hypoechoic mass resembling a porencephalic cyst as shown in Figure 3(d). TUI enabled us to detect some midline cerebral lesions which were not detected by grey scale 2D ultrasound, we detected two more cases with 3rd ventricle dilatation, one case of 4th ventricle dilatation and one case of agenesis of the corpus callosum. Serial biometric sonographic measurements together with Doppler studies of umbilical artery, and middle cerebral artery resistance indices revealed the development of asymmetric IUGR in 11 out of 19 cases (excluding the two cases who died in utero) with arrested growth of abdominal circumference, high umbilical artery resistance index (RI), or brain sparing with low resistance in middle cerebral arteries. DOI: 10.1080/14767058.2016.1245283 Prenatal ultrasound diagnosis of fetal ICH Table 1. Summary of clinical data in collected cases. Age Gest Other Postnatal Case (years) (weeks) Risk factors US findings MRI findings US findings MRI findings Clinical outcome 1 26 33 Oral anticoagulant . IVH grade III Confirmed IUGR Confirmed CP therapy . VM 2 32 27 Monoamniotic . IVH grade III Confirmed TTTS Confirmed Seizures twins 3 35 36 None . IVH grade IV Confirmed IUGR Confirmed Neonatal death . Porencephalic cyst 4 29 36 None . IVH grade III Confirmed IUGR Confirmed CP . Subdural hematoma 5 23 35 None . IVH grade II Confirmed IUGR Confirmed NCS 6 36 28 Fever . IVH grade IV Confirmed Fetal hydrops Lost Follow up NCS . Porencephalic cyst 7 22 30 None . IVH grade II Confirmed None Confirmed NCS 8 39 29 Previous affected . IVH grade IV Confirmed IUGR Confirmed Neonatal death fetus . Porencephalic cyst 9 27 29 None . IVH grade III Confirmed IUGR Lost Follow up NCS 10 31 34 None . IVH grade III Confirmed IUGR Confirmed NCS . Subdural hematoma 11 27 31 None . IVH grade III Confirmed None Confirmed Lost follow up 12 18 34 Severe . IVH grade IV Confirmed IUGR Confirmed Neonatal death preeclampsia . 4th ventricle dilatation (by TUI) . Porencephalic cyst 13 20 26 None . IVH grade III Confirmed None Confirmed NCS 14 24 27 None . IVH grade III Confirmed None Confirmed Seizures . 3rd ventricle dilatation (by TUI) 15 38 29 None . Subdural hematoma Not done None Not done IUFD 16 19 29 None . IVH grade III Confirmed IUGR Confirmed NCS . Bilateral VM 17 28 28 None . IVH grade III Confirmed IUGR Confirmed Motor deficit . Subdural hematoma 18 21 33 None . IVH grade III Confirmed ACC (by TUI) Confirmed Lost follow up 19 33 28 None . Subdural hematoma Not done None Not done IUFD 20 30 37 None . IVH grade III Confirmed IUGR Confirmed NCS 21 25 38 None . IVH grade III Confirmed None Confirmed Lost follow up . 3rd ventricle dilatation (by TUI) ACC: agenesis of corpus callosum; Gest: gestational age at which first diagnosis was made; IUGR: intrauterine growth retardation; NCS: no clinical signs (apparently normal); TTTS: twin to twin transfusion syndrome; TUI: tomographic ultrasound imaging; VM: ventriculomegaly; CP: cerebral palsy. Fetal MRI was performed in 19/21 cases between 2 and 7 (mean ± SD, 2.8 ± 2.4) days following ultrasound diagnosis. In the two cases of isolated massive subdural hematomas, fetal MRI was not done because the diagnosis was clearly obvious and both cases died in utero within the next 48 h. In all cases, fetal MRI confirmed the diagnosis of previous sonographic findings (Figure 2c). Of the 21 fetuses studied, two fetuses with early massive subdural hemorrhage died in utero and 19 cases were delivered; 14 vaginally and seven by Cesarean section (cases 1–3, 11–13, 16). The mean gestational age at which pregnancy was terminated was 36.7 ± 4.2 weeks, with a mean neonatal weight at birth of 2834 ± 985.6 g. Neonatal MRI was done in 17/19 cases, while follow up of two cases were lost after delivery. Findings matched those of prenatal fetal MRI. Discussion Our work demonstrated clear cut ultrasonographic criteria for diagnosing fetal ICH. To the best of our knowledge, this is the first study that included TUI in diagnosing fetal ICH. This modality had excellent correlation with findings in both fetal and neonatal MRIs with several advantages. TUI can demonstrate multi-parallel cutting sections on the same screen. The number and position of the slices can be adjusted with specific software controls, while optimizing hue, brightness and contrast for best image quality. Slice width can be also be modified to magnify images, and image rotation is possible [11]. We found this function to be extremely useful for detailed CNS assessment as regards to the site and size of the lesion, associated midline CNS anomalies, and ventricular dilatation. Besides being able to demonstrate the exact site and dimensions of the lesion; the volume obtained was used as a reference for follow up, and to monitor the progression of the lesion. There is no clear evidence supporting the assumption that fetal MRI is superior to the state of the art ultrasound in diagnosis of most common brain anomalies [12]. However we used this modality to confirm our ultrasound findings. Apart from clarifying parenchymal involvement in two cases, we could not reach definite conclusions concerning an additional role for fetal MRI over ultrasonography in the diagnosis of fetal ICH. In subdural hemorrhage, the ultrasound revealed an echogenic space occupying lesion with a curved boundary compressing the ipsilateral cerebral hemisphere with or M. A. Abdelkader et al. J Matern Fetal Neonatal Med, Early Online: 1–7 without ventricular compression. Similar observations have been reported by other authors [7–10,13]. In the cases of fetal IVH, the ultrasonographic features changed over time. As time progressed, the sonographic appearance of blood clots changed from homogeneously echogenic lesion separate from the choroid plexus, to a complex appearance with an external echogenic lining, and an internal sonolucent core. The more severe lesions were associated with parenchymal extension, and eventual porencephaly. Similar findings have been reported by Ghi et al. [10]. The authors also reported on the complete resolution phase, in which the appearance of a normal brain structure followed as clots disappeared and ventriculomegaly resolved. We did not encounter such a phase as most of our cases were more severe and belonged to grades III and IV. Antenatal fetal ICH may occur spontaneously, or in association with various maternal or fetal conditions. However, in the majority of cases no identifiable risk factor is found. Fetal risk factors include severe fetal hypoxia, twin–twin transfusion syndrome, demise of a co twin, congenital coagulopathy (factor V and factor X deficiency) and hemorrhage into a congenital tumor [14–19]. Maternal risk factors for fetal ICH include maternal trauma, seizures, platelet or coagulation disorders, bacterial or viral infection, maternal febrile disease, amniocentesis, medications (warfarin or cholestyramine) and drugs such as cocaine [20–22]. In our series of cases we found maternal or fetal medical conditions that might have alerted the physician to the possibility of fetal brain pathology only in (23.8%) of cases. We reported an associated finding of IUGR in 57.9% of cases. We believe that IUGR may play an important role in the pathogenesis of fetal ICH. This might be related to the immature fragile nature of the capillaries in the germinal matrix, the inadequate auto regulation of the premature autonomic nervous system, and the concomitant increase in cerebral blood flow and pressure in IUGR fetuses during times of stress [23]. In the presence of a triggering factor such as maternal anticoagulant therapy, chronic aspirin use, abruptio placenta, thrombocytopenia and maternal trauma; ICH will occur in susceptible IUGR fetuses. The medico legal significance of the prenatal diagnosis of fetal ICH should be emphasized. Those lesions might cause serious brain damage with long lasting subsequent neurological sequelae. This shows that sometimes severe brain damage can occur in the neonate, and not be caused by mismanagement of labor and delivery. Therefore, attempts to attribute poor postnatal neurologic deficit only to obstetric malpractice during labor is not justified [24]. However, the birth attendant may become a scapegoat, and bear the blame for postnatal poor neurologic outcome because of the unrecognized in utero event of ICH. This potentiates the importance of accurate prenatal sonographic diagnosis and documentation of fetal ICH before labor or delivery. It should be mentioned here that the majority of cases of fetal ICH in our series were diagnosed after 28 weeks gestation in a previously apparently normal patient at the routine scan. Since the routine fetal anomaly scan in most centers is done at 20–22 weeks, we raise the issue of another scan at the third trimester for screening patients with increased risk of fetal ICH, to detect such a late onset evolving cerebral insult. Limitations to our work included not being able to observe the long lasting effects of those serious cerebral lesions on fetuses after birth. Being a referral center; most of our cases reside in other governates, which makes neurological follow up of the neonates difficult. In conclusion, ultrasonography can be used in the detection, classification and monitoring the progression of various types of ICH. TUI is an additional diagnostic tool that might help to detect the exact size, and extent of those lesions. Although fetal MRI is not superior to US in diagnosing ICH, it might aid in the confirmation of the diagnosis. Prenatal diagnosis of fetal ICH has serious medico legal implications. Declaration of interest The authors of this study declare no conflict of interest and no competing interests with respect to the research, authorship and publication of this article. 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