First trimester screening for holoprosencephaly with choroid plexus morphology (‘butterfly’ sign) and biparietal diameter
Abstract
Objective: The aim of this study was to determine whether choroid plexus morphology (‘butterfly’ sign) and biparietal diameter (BPD) are effective sonographic screening tools for holoprosencephaly (HPE) in the first trimester. Methods: An axial view of the fetal head was obtained routinely to determine the presence of the ‘butterfly’ sign in pregnancies presenting for sonographic screening at 11–13 weeks of gestation. The same view was also used to obtain BPD measurements. The definitive diagnosis of HPE was established by the sonographic demonstration of an anterior cerebral monoventricular cavity and thalamic fusion. Results: During a 9‐year study period, 11 068 live fetuses were screened. There were 11 cases of HPE (prevalence 1/1006); all of them were detected by demonstration of an absent ‘butterfly’ sign with no false‐positive cases. The BPD was less than the 5th percentile in 40% of the cases. Conclusions: The ‘butterfly’ sign appears to be a highly sensitive marker for HPE in the first trimester. On the other hand, BPD measurements had a lower sensitivity, implying that microcephaly is not a prominent first‐trimester feature in these cases. Incorporation of the ‘butterfly’ sign into the first trimester anatomy scan is simple and can facilitate the identification of the vast majority of fetuses with HPE in the first trimester. © 2013 John Wiley & Sons, Ltd.
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The butterfly sign has a sensitivity and specificity of 100% (95% CI: 71.3-100% and 99.9-100%, respectively) for detecting holoprosencephaly.
“Careful assessment of the choroid plexus morphology should be undertaken, as the “butterfly sign” has a sensitivity and specificity of 100% (95% CI: 71.3–100% and 99.9–100%, respectively) for detecting holoprosencephaly [35].”
From First-Trimester Ultrasound: A Comparative Review of Guidelines (2026) · cites this paper as [35]
Cites
Snijders, R., Noble, P., Sebire, N., Souka, A., & Nicolaides, K. (1998) · The Lancet · doi:10.1016/s0140-6736(97)11280-6 · Cited by 1,572 · see citing works
Screening for fetal aneuploidies at 11 to 13 weeks
Nicolaides, K. H. (2011) · Prenatal Diagnosis · doi:10.1002/pd.2637 · Cited by 641 · see citing works
Increased nuchal translucency with normal karyotype
Souka, A. P., von Kaisenberg, C. S., Hyett, J. A., Sonek, J., & Nicolaides, K. H. (2005) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2004.12.093 · Cited by 514 · see citing works
Diagnostic Imaging of Fetal Anomalies
Bromley, B. (2003) · Journal of Ultrasound in Medicine · doi:10.7863/jum.2003.22.8.850 · Cited by 286 · see citing works
Brains and faces in holoprosencephaly: pre‐ and postnatal description of 30 cases
Blaas, H. ‐. K., Eriksson, A. G. Z., Salvesen, K. Å., et al. (2002) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.0960-7692.2001.00154.x · Cited by 137 · see citing works
Retronasal triangle: a sonographic landmark for the screening of cleft palate in the first trimester
Sepúlveda, W., Wong, A. E., Martínez-Ten, P., & Pérez-Pedregosa, J. (2009) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.7484 · Cited by 136 · see citing works
Self-citationThe 11–13-week scan: diagnosis and outcome of holoprosencephaly, exomphalos and megacystis
Kagan, K. O., Staboulidou, I., Syngelaki, A., Cruz, J., & Nicolaides, K. H. (2010) · Ultrasound in Obstetrics & Gynecology · doi:10.1002/uog.7646 · Cited by 108 · see citing works
First‐Trimester Sonographic Diagnosis of Holoprosencephaly
Sepúlveda, W., Víctor Dezerega, P., & Cecilia Be, R. (2004) · Journal of Ultrasound in Medicine · doi:10.7863/jum.2004.23.6.761 · Cited by 86 · see citing works
Blaas, H. ‐. K., Eik‐Nes, S. H., Vainio, T., & Isaksen, C. V. (2000) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.1469-0705.2000.00005.x · Cited by 77 · see citing works
Bernard, J. P., Cuckle, H., Stirnemann, J., Salomon, L. J., & Ville, Y. G. (2012) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2012.05.014 · Cited by 71 · see citing works
Revisiting first-trimester fetal biometry
Salomon, L. J., Bernard, J. P., Duyme, M., Dorion, A., & Ville, Y. (2003) · Ultrasound in Obstetrics & Gynecology · doi:10.1002/uog.162 · Cited by 68 · see citing works
Small biparietal diameter in fetuses with spina bifida on 11–13‐week and mid‐gestation ultrasound
Karl, K., Benoit, B., Entezami, M., et al. (2012) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.11175 · Cited by 59 · see citing works
Fetal Holoprosencephaly: Associated Malformations and Chromosomal Defects
Berry, S. M., Gosden, C. M., Snijders, R. J. M., et al. (2009) · Fetal Diagnosis and Therapy · doi:10.1159/000263552 · Cited by 56 · see citing works
Äyräs, O., Tikkanen, M., Eronen, M., Paavonen, J. A., & Stefanović, V. (2013) · Prenatal Diagnosis · doi:10.1002/pd.4143 · Cited by 54 · see citing works
Biparietal diameter at 11–13 weeks' gestation in fetuses with open spina bifida
Khalil, A. A., Coates, A., Papageorghiou, A. T., et al. (2013) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.12420 · Cited by 53 · see citing works
Peebles, D. (1998) · Prenatal Diagnosis · doi:10.1002/(sici)1097-0223(199805)18:5 · Cited by 40 · see citing works
Sepúlveda, W., Wong, A. E., & Víctor Dezerega, P. (2007) · Obstetrics and Gynecology · doi:10.1097/01.aog.0000259311.87056.5e · Cited by 36 · see citing works
Self-citationFirst‐trimester ultrasound diagnosis of holoprosencephaly: three case reports
Wong, H. S., Lam, Y. H., Tang, M., et al. (1999) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.1469-0705.1999.13050356.x · Cited by 32 · see citing works
Prenatal diagnosis of lobar holoprosencephaly
Pilu, G., Sandri, F., Perolo, A., et al. (1992) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.1469-0705.1992.02020088.x · Cited by 31 · see citing works
Intraventricular fused fornices: a specific sign of fetal lobar holoprosencephaly
Pilu, G., Ambrosetto, P., Sandri, F., et al. (1994) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.1469-0705.1994.04010065.x · Cited by 29 · see citing works
Early diagnosis of holoprosencephaly
Nelson, L. H., & King, M. D. (1992) · Journal of Ultrasound in Medicine · doi:10.7863/jum.1992.11.1.57 · Cited by 28 · see citing works
Prenatal diagnosis of alobar holoprosencephaly at 10 weeks of gestation
Turner, C. D., Silva, S., & Jeanty, P. (1999) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.1469-0705.1999.13050360.x · Cited by 25 · see citing works
First trimester diagnosis of cyclopia and holoprosencephaly.
van Zalen-Sprock, R. M., van Vugt, J. M. G., van der Harten, H. J., et al. (1995) · Journal of Ultrasound in Medicine · doi:10.7863/jum.1995.14.8.631 · Cited by 23 · see citing works
First trimester sonographic diagnosis of holoprosencephaly
Tongsong, T., Wanapirak, C., Chanprapaph, P., et al. (1999) · International Journal of Gynecology & Obstetrics · doi:10.1016/s0020-7292(99)00059-4 · Cited by 19 · see citing works
Sepúlveda, W. (2009) · Journal of Ultrasound in Medicine · doi:10.7863/jum.2009.28.8.1077 · Cited by 16 · see citing works
Holoprosencephaly at 9 Weeks 6 Days in a Triploid Fetus
Sepúlveda, W., Lutz, I., & Cecilia Be, R. (2007) · Journal of Ultrasound in Medicine · doi:10.7863/jum.2007.26.3.411 · Cited by 11 · see citing works
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Wagner, P., Sonek, J., Hoopmann, M., Abele, H., & Kagan, K. O. (2016) · Ultrasound in Obstetrics & Gynecology · doi:10.1002/uog.15829 · Cited by 68 · see citing works
First‐trimester fetal neurosonography: technique and diagnostic potential
Volpe, N., Dall’Asta, A., di Pasquo, E., Frusca, T., & Ghi, T. (2020) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.23149 · Cited by 70 · see citing works
Sonographic detection of central nervous system defects in the first trimester of pregnancy
Engels, A., Joyeux, L., Brantner, C., Keersmaecker, B. D., Catte, L. D., Baud, D., Deprest, J. A., & Mieghem, T. V. (2016) · Prenatal Diagnosis · doi:10.1002/pd.4770 · Cited by 62 · see citing works
Stümm, M., Entezami, M., Haug, K., Blank, C., Wüstemann, M., Schulze, B., Raabe‐Meyer, G., Hempel, M., Schelling, M., Ostermayer, E., et al. (2013) · Prenatal Diagnosis · doi:10.1002/pd.4278 · Cited by 42 · see citing works
Chaoui, R., Benoit, B., Entezami, M., Frenzel, W., Heling, K. S., Ladendorf, B., Pietzsch, V., Lopez, A. S., & Karl, K. (2019) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.20856 · Cited by 42 · see citing works
Simon, E. G., Arthuis, C., Haddad, G., Bertrand, P., & Perrotin, F. (2014) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.13406 · Cited by 37 · see citing works
Sonographic spectrum of first‐trimester fetal cephalocele: review of 35 cases
Sepúlveda, W., Wong, A. E., En, A., Odegova, N., Martínez-Ten, P., & Meagher, S. (2014) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.14661 · Cited by 35 · see citing works
Self-citationMonteagudo, A. (2020) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2020.08.178 · Cited by 36 · see citing works
(2020) · Journal of Ultrasound in Medicine · doi:10.1002/jum.15477 · Cited by 38 · see citing works
Volpe, N., Şen, C., Turan, Ş., Sepúlveda, W., Khalil, A. A., Rolnik, D. L., Robertis, V. D., Volpe, P., Gil, M. M., Chaveeva, P., et al. (2022) · Journal of Perinatal Medicine · doi:10.1515/jpm-2022-0125 · Cited by 33 · see citing works
Buijtendijk, M. F., Bet, B. B., Leeflang, M. M., Shah, H., Reuvekamp, T., Goring, T., Docter, D., Timmerman, M. G., Dawood, Y., Lugthart, M. A., et al. (2024) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd014715.pub2 · Cited by 47 · see citing works
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Ungureanu, D. R., Drăgușin, R. C., Căpitănescu, R. G., Zorilă, L., Ofițeru, A. M. I., Marinaș, C., Pătru, C. L., Comănescu, A. C., Comănescu, M. C., Sîrbu, O. C., et al. (2023) · Brain Sciences · doi:10.3390/brainsci13010118 · Cited by 20 · see citing works
Karim, J. N., Mascio, D. D., Roberts, N. W., Papageorghiou, A. T., & study, F. T. A. (2024) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.27649 · Cited by 22 · see citing works
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Monteagudo, A., Kuller, J. A., Craigo, S., et al. (2020) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2020.08.041 · Cited by 18 · see citing works
Katorza, E., Gat, I., Duvdevani, N., Meller, N., Pardo, N., Barzilay, E., & Achiron, R. (2017) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767058.2017.1289165 · Cited by 17 · see citing works
Rodriguez, N., Casasbuenas, A., En, A., et al. (2018) · Journal of Ultrasound in Medicine · doi:10.1002/jum.14759 · Cited by 15 · see citing works
Self-citationHo, Y., Herrero, T. C., Aguinaldo, J., et al. (2019) · Journal of Ultrasound in Medicine · doi:10.1002/jum.15086 · Cited by 13 · see citing works
Sepúlveda, W., Wong, A. E., En, A., Odegova, N., Martínez-Ten, P., & Meagher, S. E. (2014) · Journal of Ultrasound in Medicine · doi:10.7863/ultra.33.7.1165 · Cited by 11 · see citing works
Self-citationPrenatal Detection of Fetal Anomalies at the 11- to 13-Week Scan—Part I: Brain, Face and Neck
Illescas, T., Sepúlveda, W., Adiego, B., & Martínez-Ten, P. (2013) · Donald School Journal of Ultrasound in Obstetrics & Gynecology · doi:10.5005/jp-journals-10009-1307 · Cited by 10 · see citing works
Sonography of fetal holoprosencephaly: a guide to recognize the lesser varieties
Montaguti, E., Cariello, L., Brunelli, E., Youssef, A., Livi, A., Salsi, G., & Pilu, G. (2022) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767058.2022.2050900 · Cited by 10 · see citing works
Cospain, A., Faoucher, M., Cauchois, A., et al. (2022) · Pediatric and Developmental Pathology · doi:10.1177/10935266221095305 · Cited by 9 · see citing works
Simon, E. G., Arthuis, C., Haddad, G., Bertrand, P., & Perrotin, F. (2014) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.13764 · Cited by 7 · see citing works
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Hoopmann, M., & Kagan, K. O. (2017) · Ultraschall in der Medizin - European Journal of Ultrasound · doi:10.1055/s-0035-1567238 · Cited by 6 · see citing works
Prasad, S., Fabrizio, C. D., Eltaweel, N. A., et al. (2023) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.26189 · Cited by 6 · see citing works
Karim, J. N., Campbell, H., Pandya, P., Wilson, E. C. F., Alfirevic, Z., Chudleigh, T., Duff, E., Fisher, J., Goodman, H., Hinton, L., et al. (2025) · Health Technology Assessment · doi:10.3310/nltp7102 · Cited by 5 · see citing works
Biparietal diameter at 11 to 13 weeks' gestation in fetuses with holoprosencephaly
Khalil, A. A., Papageorghiou, A. T., Bhide, A., Akolekar, R., & Thilaganathan, B. (2013) · Prenatal Diagnosis · doi:10.1002/pd.4269 · Cited by 6 · see citing works
Rajs, B., Pasternok, M., Nocuń, A., Matyszkiewicz, A., Ziętek, D., Rozmus-Warcholińska, W., Zalewski, S., Migda, M., Mavrikis, J., & Wiechec, M. T. (2019) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767058.2019.1623779 · Cited by 5 · see citing works
Sepúlveda, W., Garcia‐Rodriguez, R., Martínez-Ten, P., Tonni, G., Grisolia, G., & Meagher, S. E. (2023) · Journal of Clinical Ultrasound · doi:10.1002/jcu.23337 · Cited by 4 · see citing works
Hinreiner, S., Wieczorek, D., Mueller, D., et al. (2018) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31625 · Cited by 4 · see citing works
“The incidence of HPE varies throughout pregnancy decreasing from 1:250 in early embryos to 1:10,000 in live births (Sepulveda & Wong, 2013).”
BackgroundOh, S., Hong, J. S., Seol, H., Hwang, H. S., Park, H. S., Kim, K., Ko, H. S., Kwak, D.-W., Kim, M. Y., Park, M. H., et al. (2015) · Obstetrics & Gynecology Science · doi:10.5468/ogs.2015.58.1.1 · Cited by 4 · see citing works
Sabu, B., Raja, V., Srinivasan, L., et al. (2021) · Journal of Fetal Medicine · doi:10.1007/s40556-020-00284-1 · Cited by 2 · see citing works
The First-Trimester Fetal Head and Brain
Monteagudo, A., & Timor‐Tritsch, I. E. (2023) · Springer eBooks · doi:10.1007/978-3-031-24133-8_19 · Cited by 2 · see citing works
Sepúlveda, W., Garcia-Rodriguez, R., Nilo, C., et al. (2025) · Springer eBooks · doi:10.1007/978-3-031-96947-8_17 · Cited by 1 · see citing works
Self-citationValle, L. D., Pilu, G., Khalil, A. A., et al. (2026) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.70133 · Cited by 1 · see citing works
The Fetal Brain in Fetuses with Orofacial Abnormalities
Malinger, G. (2017) · Springer eBooks · doi:10.1007/978-3-319-32516-3_9 · Cited by 1 · see citing works
Monteagudo, A., Dziadosz, M., & Timor‐Tritsch, I. E. (2015) · Springer eBooks · doi:10.1007/978-3-319-20203-7_19 · Cited by 1 · see citing works
(2022) · Revista Venezolana de Ultrasonido en Medicina · doi:10.57097/revum.2022.2.3.7 · Cited by 1 · see citing works
Prenatal Diagnosis of Fetal Malformations by Ultrasound
Ville, Y. G., & Bault, J. ‐. (2015) · doi:10.1002/9781118981559.ch13 · Cited by 1 · see citing works
First-Trimester Ultrasound: A Comparative Review of Guidelines
Boureka, E., Tsakiridis, I., Michos, G., Liberis, A., Giouleka, S., Mamopoulos, A., Kalogiannidis, I., & Dagklis, T. (2026) · Diagnostics · doi:10.3390/diagnostics16111695
Kagan, K. O., & Hoopmann, M. (2020) · Elsevier eBooks · doi:10.1016/b978-3-437-21901-6.00001-4
Ghasemi, T., Roostaee, A., Lima, Z. S., et al. (2022) · Medical Science · doi:10.54905/disssi/v26i127/ms374e2351
Dahmardeh, H., Mirgaloybayat, S., Hasanpoor, S., et al. (2022) · Zahedan Journal of Research in Medical Sciences · doi:10.5812/zjrms-119002
Three-Dimensional Ultrasound: A Role in Early Pregnancy?
Ximenes, R. L. D. S., Peters, R., & Gonçalves, L. F. (2023) · Springer eBooks · doi:10.1007/978-3-031-24133-8_14
Volpe, N., Dall’Asta, A., Morganelli, G., et al. (2024) · Ultrasound in Obstetrics and Gynecology · doi:10.1007/978-3-031-70192-4_13
Montaguti, E., & Pilu, G. (2024) · Ultrasound in Obstetrics and Gynecology · doi:10.1007/978-3-031-70192-4_3
Normal Anatomy of the Fetal Brain and Spine: Screening Planes and Fetal Neurosonography
Robertis, V. D., Fanelli, T., Bosco, M., & Volpe, P. (2024) · Springer eBooks · doi:10.1007/978-3-031-70192-4_1
Xue, X., Tu, P., Zhang, X., et al. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1637954
The Fetal Brain in Fetuses with Orofacial Abnormalities
Malinger, G., Stern, J., & Haratz, K. K. (2025) · Springer eBooks · doi:10.1007/978-3-031-96947-8_12
Kagan, K. O., & Hoopmann, M. (2026) · Elsevier eBooks · doi:10.1016/b978-3-437-21339-7.00001-2
First-trimester fetal neurosonography
Sharma, S., Sanyal, A., & Khalil, A. A. (2026) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2026.102759
- Authors
- Sepulveda, W., & Wong, A. E.
- Affiliations
- Fetal Medicine Center, Department of Obstetrics and Gynecology Clinica Las Condes Santiago Chile
- Clínica Las Condes (CL)
- ORCID
- Wong, Amy E.
- Venue
- Prenatal Diagnosis
- Publisher
- Wiley
- Published
- 2013-10-04
- Volume
- 33
- Issue
- 13
- Pages
- 1233-1237
- ISSN
- 0197-3851 (ISSN-L)
- 1097-0223
- OpenAlex
- W1916065822
- Semantic Scholar
- 55dd63a60c828cf2994a3c09ea4d6022037171a0
- Cited by
- 49
- References
- 26
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 1 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 1 · 2015: 4 · 2014: 4 · 2013: 3
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Prenatal Diagnosis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Screening and Diagnostics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Spinal Dysraphism and Malformations
- Keywords
- holoprosencephaly, biparietal diameter, first-trimester screening, prenatal ultrasound, microcephaly
- MeSH terms
- Adolescent, Adult, Body Weights and Measures, Chile, Choroid Plexus, Female, Head, Humans, Middle Aged, Parietal Lobe, Pregnancy, Pregnancy Trimester, First, Prevalence, Holoprosencephaly, Ultrasonography, Prenatal, Young Adult
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