Antenatal ultrasound (AUS) and the detection of cranio- and orofacial malformations—a scoping review
Highlight box
Key findings
• Gestational ultrasound (GUS) scans are effective in detecting multiple orofacial abnormalities, in multiple gestational ages.
• Frequently detected anomalies included facial clefts, palate deformities, micrognathia, and glossoptosis.
What is known and what is new?
• GUS are used to diagnose congenital abnormalities, mostly related to the cardiovascular, respiratory, and gastrointestinal systems. Before our study, data on the applicability of GUS for detecting craniofacial abnormalities and anomalies were disaggregated and available in individual reports.
• There is a universe of information that can be observed in GUS scans, such as the establishment and maturation of functions (swallowing, sucking and breathing), vicious positions and risk of asymmetries, development of the arches and face, which could be observed in these exams that are performed.
• Collaborative and patient centred care delivery among different health care professionals is needed to better identify and manage orofacial disorders.
What is the implication, and what should change now?
• Better utilization of GUS would aid in better diagnosis of orofacial abnormalities.
• Routine application of a digital technologies in regular antenatal ultrasounds can help in detailed and precise evaluations to identify neonatal orofacial malformations.
• The early identification of major craniofacial abnormalities might aid the decision making towards termination of pregnancy.
• Early identification of craniofacial abnormalities can help identify potential interventions the neonate might need in the future.
Introduction
Gestational ultrasounds (GUS), commonly referred to as “antenatal ultrasounds” (AUS), have been considered one of the most useful, cost-effective, and sustainable imaging techniques in obstetrics (1). Based on official recommendations endorsed by the Departments of Reproductive Health and Research, Nutrition for Health and Development, and Maternal, Newborn, Child and Adolescent Health of the World Health Organization (WHO), GUS are internationally recommended to be carried out before 24 weeks of gestational (also known as “early ultrasound”). The results derived from this early evaluation are useful in evaluating fetal growth parameters (2), early detection and the monitoring of fetal anomalies, recognizing the presence of multiparity, or identifying structural deviations relevant for the unborn child (3). Additionally, GUS scans have generated positive health-related outcomes in relation to a reduced induction of labor for post-term pregnancy, in addition to enhancing women’s gestational experiences in general (4). Nevertheless, a growing global trend in performing multiple fetal scans either during the mother’s first contact with medical personnel (up to 12 weeks of gestation) or during the third gestational trimester have been reported elsewhere (5). To note, as emphasized in the latest WHO list of recommendations on antenatal care for positive pregnancy experiences, the frequency and exact timing of antenatal care procedures should be aligned with local context, populational singularities, as well as relevant healthcare system characteristics (6).
In recent years, several publications (including systematic reviews and evidence-based guidelines) have reported data on the performance of AUS in detecting systemic fetal diseases and predicting postnatal outcomes (7-11). The International Society of Ultrasound in Obstetrics and Gynecology guidelines, a multicenter study involving more than 14 European countries, reported an overall accuracy of 56% in detecting major fetal anomalies through routine mid-trimester ultrasonographic examination in unselected populations (12,13). In addition, as suggested by Morris and colleagues in 2009, antenatal scans showed moderate performance in predicting postnatal renal function in congenital lower urinary tract obstruction, with sensitivity of 0.57 [95% confidence interval (CI): 0.37–0.76], specificity of 0.84 (95% CI: 0.71–0.94), and area under the curve of 0.78 (7). Likewise, a high-quality Cochrane-associated systematic review and meta-analysis (11) addressing the importance of routine ultrasounds (US) reported results from only one clinical trial from 1993 (14), which evaluated the rates of fetal abnormalities at the third gestational trimester. However, no additional emphasis was given to the relevance of the technique in detecting cranio- and orofacial fetal abnormalities.
Across the globe, there is an ongoing trend for policymakers and healthcare providers to prioritize oral health diseases and conditions, which are greatly preventable and suitable for early treatment. In this regard, multiple social actors have pioneered the global oral health status scene. For example, the Department of Noncommunicable Diseases, Universal Health Coverage/Communicable and Noncommunicable Diseases of the WHO stated that almost all countries (among the 194 WHO Member States) implemented actions for screening programs for early detection of oral diseases (15). More specifically, multiple enthusiasts in the field of dentistry, maxillofacial imaging, and oral pathology have demonstrated the potential and suitable correlation between GUS, the early detection of abnormalities, and the prompt and timely delivery of care as a promising approach within the field of public health (16). To date, several reports have suggested the effectiveness of GUS in recognizing oral abnormalities, including the presence of craniofacial asymmetries, oral dysfunctions, and minor or major pathologies (16). However, existing literature is fragmented and not adequately integrated. Consequently, there is an existing need for knowledge organization and aggregation to systematically clarify the current potential of AUS in early detecting oral abnormalities and orofacial malformations. Therefore, this scoping review seeks to evaluate and compile available evidence from primary studies regarding the applicability of GUS in detecting neonatal oral and craniofacial malformations. It is expected that this review will lay the foundation for more focused studies within this very under-studied area to expand the utilization and application of AUS worldwide. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://jphe.amegroups.com/article/view/10.21037/jphe-24-59/rc).
Methods
Review protocol and followed guidelines
This scoping review strictly adhered to the methodological guidelines for conducting a scoping review, primarily endorsed by Arksey and O’Malley (17). Additionally, this report followed the Joanna Briggs Institute Manual for Evidence Synthesis for Scoping Reviews (18). It is important to note that all of our results were reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) (19). Before starting our reviewing process, we registered our protocol on PROSPERO (CRD42022341553) (20).
Search strategy and selection criteria
Our searches were conducted in the four leading scientific medical and dental-related databases (Embase, MEDLINE®, Web of Sciences, and the Cochrane Library). Two independent authors screened titles and abstracts for eligible studies. Additionally, identified pre-selected studies were further evaluated for eligibility. We considered studies eligible if they: (I) reported the detection (with or without emphasizing the performance metrics) of cranio- and orofacial anomalies identified through AUS (either via 2-, 3-, or 4-dimensional scans); (II) enrolled pregnant women from the first to third trimester of gestation; and (III) enrolled at least 345 patients (either referred as pregnant individuals or fetuses). It is important to state that those studies reporting orofacial abnormalities as a subgroup of a major group of abnormalities (i.e., concomitant to reporting of cardiovascular, respiratory), were also considered valid, if the aforementioned criteria were met. However, for these studies reporting multiple malformations and fetal abnormalities, only the section regarding the identification of orofacial anomalies was extracted.
Moreover, we accepted original studies if they compared the use of morphological US to no intervention, magnetic resonance imaging, or any other diagnostic method to verify the existence of oral malformation during gestation, at any study design (including observational and randomized clinical trials). However, if a primary study did not compare the findings associated with AUS with another radiological or anatomical assessment arm, we also considered it eligible for inclusion. We did not exclude publications based on published language or publication date. We excluded conference proceedings, editorials, correspondences, and data not published in the format of an original research study. In addition, studies focusing on a subset of population patients (such as pregnant women expecting syndromic fetuses) were excluded.
Screening process was carried out throughout Covidence®. A third party solved decisional conflicts. Search terms involved “Morphological Ultrasound”, “Prenatal Ultrasound”, “Facial Anomalies”, “Craniofacial Abnormalities”, and associated synonymous search identifiers. Our search was performed from database inception until October 2023. The search strategy (available in Appendix 1) was designed in collaboration with a group of experts and the information specialist. Bibliographies of records shortlisted for full-text analysis were evaluated to ensure an exhaustive search.
Data extraction
Included records underwent full data extraction by two review researchers, independently. Elementary data from included studies were abstracted, including (I) study identification; (II) publication year; (III) journal name; (IV) study design; (V) study objective; (VI) the number of included individuals being reported and evaluated; and (VII) setting and country where the study was carried out. In addition, as outlined in our protocol, the extracted and evaluated primary outcomes consisted of (I) the type of craniofacial morphology primarily considered and reported within the study; (II) number of detected cases among the total study sample; and (III) performance metrics associated with the performance of AUS; (IV) the main findings raised in each publication; (V) technical difficulties related to the execution of AUS; and (VI) implications of reported findings in maternal health and birth outcomes. For each included study, at least two investigators assessed the extracted data. Conflicts were resolved by discussion.
Data analysis and summarization
As primarily stated in our protocol, we performed a descriptive assessment of the acquired data and reported a summary of data as a written-based text. For those studies reporting performance metrics (including accuracy values, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios) we reported the range of identified values per type of abnormality. The same approach (descriptive reporting) for primary studies reporting prevalence values was carried out. The synthesis of relevant data among included studies is shown in Tables 1-3.
Table 1
Study ID | Publication year | Study design | Involved patients | Gestational weeks | Country | Journal | Objective |
---|---|---|---|---|---|---|---|
Aldridge (21) | 2023 | Observational study (retrospective cohort) | 12,694 pregnancies | N/A | UK | BJOG | To measure condition-specific detection rates for 14 physical conditions screened for by the NHS FASP FA ultrasound scan |
Bardi (22) | 2019 | Observational study (retrospective cohort) | 13,417 pregnancies | Pregnancies from 110/7 to 116/7 weeks of gestation | The Netherlands | Fetal Diagn Ther | To assess the percentage and type of congenital anomalies diagnosed at first trimester US scan in a primary care setting without following a standardized protocol for fetal anatomical assessment |
Bister (23) | 2011 | Observational study (retrospective cohort) | 23,577 pregnancies | Pregnancies from 180/7 to 206/7 weeks of gestation | UK | Eur J Orthod | To determine the incidence of facial clefting in the Cambridge (UK) area and to ascertain the accuracy of AUS detection |
Bronshtein (24) | 2005 | Observational study (retrospective cohort) | 8,000 pregnancies | Pregnancies from 140/7 to 246/7 weeks of gestation | Israel | Am J Obstet Gynecol | To describe the sonographic features of fetal glossoptosis in the Pierre Robin sequence |
Bronshtein (25) | 1998 | Observational study (retrospective cohort) | 25,114 transvaginal and transabdominal sonographies | Pregnancies from 120/7 to 276/7 weeks of gestation | Israel | Prenat Diagn | To describe the prenatal detection of fetal nasal abnormalities by ultrasound |
Bronshtein (26) | 1994 | Observational study (retrospective cohort) | 14,988 fetuses | Pregnancies from the early second trimester | Israel | Obstet Gynecol | To describe the detection of cleft lip in the early second trimester using transvaginal sonography |
Cash (27) | 2001 | Observational study (retrospective cohort) | 27,708 anomaly ultrasound examinations | Pregnancies at 80/7 to 126/7 weeks and at 180/7 to 206/7 weeks of gestation | UK | Ultrasound Obstet Gynecol | To evaluate the accuracy of prenatal ultrasound in the detection of facial clefts in a low-risk screening population and to report on the outcome of these pregnancies |
Chelemen (28) | 2010 | Observational study (retrospective cohort) | 2,976 pregnancies | Pregnant women in the first, second, and third semester of gestation | UK | Obstetrica si Ginecologie | To inform the health care system involved in assisting the obstetrical population about the currently important impact of major fetal structural abnormalities on public health through their incidence and severity in order to develop new and more efficient preventive actions |
Clementi (29) | 2000 | Observational study (retrospective cohort) | 7,758 fetuses | Pregnant women in the first and third semester of gestation | Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK, Ukraine | Prenat Diagn | To evaluate prenatal detection of CL(P) and CP. All CL(P) and CPs suspected prenatally and identified at birth in the period 1996–1998 were registered from 20 Congenital Malformation Registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK, Ukraine |
Gai (30) | 2022 | Observational study (retrospective cohort) | 110,286 women medical records (334 infants) | N/A | China | BMC Med Imaging | To report the predictive probabilities of prenatal US and MRI in the diagnosis of OFCs using larger sample sizes and to compare the diagnostic values of prenatal US and MRI in the classification of OFCs |
Hafner (31) | 1997 | Observational study (retrospective cohort) | 5,407 pregnancies | Pregnant women with 226/7 weeks of gestation | Austria | Prenat Diagn | To conduct a prospective trial to shed light on the incidence of facial malformations, on the prenatal detection rate and on the clinical implications of their detection |
Hegge (32) | 1986 | Observational study (retrospective cohort) | 7,100 obstetric examinations | N/A | USA | J Ultrasound Med | To address the question of whether an examination of the fetal face should he included in the fetal anatomy survey during obstetric sonography |
Hjort-Pedersen (33) | 2023 | Observational study (retrospective cohort) | 19,367 fetuses | Pregnant women on the second and third trimester | Denmark | Acta Obstet Gynecol Scand | To investigate the performance of the second-trimester ultrasound scan regarding ultrasound-detectable congenital malformations in a Danish region |
Kelekci (34) | 2004 | Observational study (retrospective cohort) | 642 pregnancies | Pregnant women from 110/7 to 146/7 weeks of gestation | Turkey | Gynecol Obstet Invest | To present our preliminary data about nasal bone measurements at 11–14 weeks of pregnancy |
Kong (35) | 2017 | Observational study (retrospective cohort) | 6,432 ultrasound examinations | Pregnant women at 186/7 and 206/7 weeks or later at scheduled follow-up visit | China | Clinical and Experimental Obstetrics & Gynecology | To assess the prenatal prevalence of congenital malformations and the different types and to determine rate of perinatal mortality |
Lachmann (36) | 2018 | Observational study (retrospective cohort) | 1,087 fetuses | Pregnant women from 110/7 to 136/7 weeks scan | Germany | Fetal Diagn Ther | To evaluate the maxillary gap sign and describe markers for the first-trimester diagnosis of isolated CLP at 11–13 weeks |
Lakshmy (37) | 2020 | Observational study (retrospective cohort) | 9,576 singleton fetuses | Pregnancy between 120/7 and 206/7 weeks of gestation | India | Ultrasound Obstet Gynecol | To describe a novel sign, the ‘superimposed-line’ sign, for early diagnosis of cleft of the fetal secondary palate on two-dimensional imaging of the vomer maxillary junction in the midsagittal view |
Lakshmy (38) | 2017 | Observational study (retrospective cohort) | 2,014 pregnancies | Pregnant women from 110/7 to 136/7 weeks of gestation | India | J Ultrasound Med | To describe a sonographic technique based on 2D markers for screening of palatine clefts during the nuchal translucency scan and to assess the ability of 3-dimensional sonography in imaging the normal and abnormal palate |
Leiroz (39) | 2021 | Observational study (retrospective cohort) | 967 pregnancies | Pregnant women from 200/7 to 246/7 weeks of gestation | Brazil | J Gynecol Obstet Hum Reprod | To assess the performance of a basic mid-trimester fetal ultrasound scan protocol for the diagnosis of congenital anomalies by calculating its accuracy, sensitivity, and specificity |
Li (40) | 2008 | Observational study (retrospective cohort) | 993 fetuses | Neonates and babies with malformation | China | Zhongguo Yi Xue Ke Xue Yuan Xue Bao | To study the value of the prenatal ultrasound in the diagnosis of fetal malformation |
Li (41) | 2023 | Observational study (retrospective cohort) | 7,336 fetuses—18 CLP in first trimester | First trimester fetuses | China | Curr Med Imaging | To study MTHSM by 2-dimensional sonography in the screening of fetal CLP during the nuchal translucency scans |
Liao (42) | 2021 | Observational study (retrospective cohort) | 59,349 pregnancies | Pregnant women from 110/7 to 136/7 weeks of gestation | China | Am J Obstet Gynecol | To determine the performance of routine first trimester scans using a standardized anatomical protocol for detecting structural abnormalities in China |
Liao (43) | 2023 | Observational study (retrospective cohort) | 300 fetuses without CLP (8,538 high risk fetuses) | Pregnant women from 120/7 to 206/7 weeks of gestation | China | Cleft Palate Craniofac J | To establish normal values of palatal bone growth in fetuses at different gestational weeks in the early stages of the second trimester and to explore the clinical application value of the four-step ultrasound screening method for fetal cleft lip and palate |
Lind (44) | 2015 | Observational study (retrospective cohort) | 166,000 pregnancies | N/A | France | Prenat Diagn | To assess the outcome of fetuses who had sonographic features suggestive of PRS |
Liu (45) | 2017 | Observational study (retrospective cohort) | 3,795 fetuses (3,672 pregnancies) | Pregnant women from 110/7 to 136/7 weeks of gestation | China | Clin Exp Obstet Gynecol | To explore the ultrasonographic methods towards CLP in first trimester |
Luedders (46) | 2011 | Observational study (retrospective cohort) | 28,935 pregnancies | N/A | Germany | Prenat Diagn | To determine the accuracy and characteristics of prenatally detected fetal micrognathia |
Maarse (47) | 2011 | Observational study (retrospective cohort) | 35,924 low-risk and 2,836 high-risk pregnant women | Pregnant women at the second trimester of gestation | The Netherlands | Ultrasound Obstet Gynecol | To evaluate the sensitivity and specificity of ultrasound for detecting prenatal facial clefts in low-risk and high-risk populations |
Merz (48) | 1997 | Observational study (retrospective cohort) | 618 high-risk pregnancies | Pregnancies between 90/7 and 376/7 weeks of gestation | Germany | Ultrasound Obstet Gynecol | To evaluate fetal anomalies by two-dimensional and three-dimensional ultrasound imaging as part of a level III screening evaluation |
Moreira (49) | 2023 | Observational study (retrospective cohort) | 672 fetuses | N/A | Portugal | Congenital Anomalies | To describe the prevalence of family history in patients with orofacial clefts and analyze prenatal diagnosis inpatients born before 2001, between 2001 and 2007 and after 2007 |
Offerdal (50) | 2008 | Observational study (retrospective cohort) | 49,314 pregnancies | N/A | Norway | Ultrasound Obstet Gynecol | To evaluate prenatal detection of facial clefts by ultrasound in a large non-selected population, and to study trends in detection rates over 18 years |
Paaske (51) | 2018 | Observational study (retrospective cohort) | 182,907 fetuses | Pregnant women over 20 weeks of gestation | Denmark | Eur J Med Genet | To describe the prevalence of cleft lip with or without cleft palate and cleft palate in a Danish area and to describe associated anomalies and the development in prenatal diagnosis over time |
Paterson (52) | 2011 | Observational study (retrospective cohort) | 459 pregnancies | N/A | UK | Cleft Palate Craniofac J | To determine the proportion of children with cleft lip and/or cleft palate diagnosed prenatally between 1999 and 2008 in those referred for treatment to the RHSC in Glasgow, Scotland; and to compare the percentage prenatally diagnosed in 2008 versus other cleft treatment centers in the UK |
Pilalis (53) | 2012 | Observational study (retrospective cohort) | 3,902 pregnancies | Pregnant women at 110/7 to 146/7 and 200/7 to 246/7 weeks of gestation | Greece | J Matern Fetal Neonatal Med | To evaluate a two-step screening protocol of ultra-sound examinations (11–14 and 20–24 weeks) for the detection of major fetal structural defects |
Rabie (54) | 2019 | Observational study (retrospective cohort) | 3,145 ultrasounds were performed on-site, and 2,368 ultrasounds were performed remotely | Pregnant women over 170/7 weeks of gestation | USA | Australas J Ultrasound Med | To compare the sensitivity and accuracy of teleultrasound to on-site ultrasound, and to demonstrate that teleultrasound |
Rodríguez Dehli (55) | 2010 | Observational study (retrospective cohort) | 103,452 births | N/A | Spain | An Pediatr (Barc) | To assess the prevalence of oral clefts and to describe the associated malformations in a geographically defined population |
Rotten (56) | 2002 | Observational study (retrospective cohort) | 371 normal fetuses and 12 abnormal fetuses | Pregnant women from 180/7 to 286/7 weeks of gestation | France | Ultrasound Obstet Gynecol | To define parameters that enable the objective diagnosis of anomalies of the position and/or size of the fetal mandible in utero |
Shaikh (57) | 2022 | Observational study (retrospective cohort) | 250,000 ultrasound examinations | Pregnant women at 20 weeks of gestation | UK | Int J Environ Res Public Health | To compare the severity of the cleft lip and palate detected by ultrasound scanning of the fetus with the severity at birth |
Stoll (58) | 2000 | Observational study (retrospective cohort) | 265,679 consecutive births | Pregnant women from 100/7 to 306/7 weeks of gestation | France | Ann Genet | To evaluate the effectiveness of prenatal diagnosis using routine ultrasonographic examination for the screening and prevention of oral clefts (cleft lip/palate) |
Suresh (59) | 2006 | Observational study (retrospective cohort) | 500 pregnant women + 34,211 ultrasound examinations | Pregnant women from 180/7 to 226/7 weeks of gestation | India | J Ultrasound Med | To describe a technique to improve the diagnostic accuracy of facial clefts (lip and palate) and to assess the feasibility of including this technique as part of standard protocol during targeted imaging |
Syngelaki (60) | 2011 | Observational study (retrospective cohort) | 45,191 pregnancies | Pregnant women from 110/7 to 136/7 weeks of gestation | UK | Prenat Diagn | To examine the performance of the 11–13 weeks scan in detecting non-chromosomal abnormalities |
Takita (61) | 2016 | Observational study (retrospective cohort) | 2,028 singleton babies | Pregnant women in the first (11 to 136/7 weeks) and second trimester (18 to 206/7 weeks) of gestation | Japan | J Med Ultrason | To assess the usefulness of antenatal ultrasound examinations for detecting fetal morphological abnormalities in the first and second trimesters |
Tang (62) | 2012 | Observational study (retrospective cohort) | 13,611 pregnant women | Pregnant women from 11 to 136/7 weeks of gestation | China | Chinese Journal of Medical Imaging Technology | To assess the feasibility of ultrasound in diagnosis of fetus face malformations in early gestation |
Trout (63) | 1994 | Observational study (retrospective cohort) | 422 structurally normal fetuses | Pregnant women from 120/7 to 376/7 weeks of gestation | USA | J Ultrasound Med | To establish the validity of previously developed orbital nomogram for high-risk population and to determine whether proved cases of hypotelorism and hypertelorism fell outside normal ranges |
Vial (64) | 2001 | Observational study (retrospective cohort) | 512 malformations, 38,110 births | Pregnant women in three time-points (early scan—110/7 to 146/7 weeks of gestation, second scan—200/7 to 226/7 weeks of gestation, and third scan—320/7 to 346/7 weeks of gestation) | Switzerland | Swiss Med Wkly | To determine the sensitivity of ultrasonography in screening and detection of fetal malformations in pregnant women |
Wayne (65) | 2002 | Observational study (retrospective cohort) | 17,551 pregnant women | Pregnant women from 180/7 to 236/7 weeks of gestation | UK | Br J Radiol | To determine the sensitivity and accuracy of routine second trimester ultrasound screening for facial clefts |
Weedn (66) | 2014 | Observational study (retrospective cohort) | 4,013 pregnant women | Pregnant women over 20 weeks of gestation | USA | Birth Defects Res A Clin Mol Teratol | To determine the frequency of maternal reporting of abnormal prenatal ultrasound for selected birth defects and to investigate associated maternal characteristics using data from the NBDPS |
Weiner (67) | 2007 | Observational study (retrospective cohort) | 1,723 | Pregnant women from 140/7 to 166/7 weeks of gestation† | USA and Israel | Am J Obstet Gynecol | To evaluate the ability to screen for structural fetal anomalies during the NT ultrasound examination, without performing a complete anatomic fetal scan, by using the sagittal views of the fetus |
Wilhelm (68) | 2010 | Observational study (retrospective cohort) | 667 pregnant women | Pregnant women from 200/7 to 256/7 weeks of gestation | N/A | Ultrasound Obstet Gynecol | To determine the feasibility of visualization of the uvula and the soft palate during routine 2D ultrasound examination and to develop a sonographic procedure that facilitates prenatal detection of isolated fetal cleft palate |
Zhen (69) | 2021 | Observational study (retrospective cohort) | 19,800 scans | Pregnant women from 110/7 to 146/7 weeks of gestation | China | Eur J Obstet Gynecol Reprod Biol | To evaluate the prognosis of fetuses with a prenatal diagnosis of micrognathia in the first trimester |
Zheng (70) | 2018 | Observational study (retrospective cohort) | 2,982 fetuses (315 twins) | Pregnant women from 180/7 to 246/7 weeks of gestation | China | Prenat Diagn | To evaluate the possibility of obtaining the axial view of maxilla and to evaluate the performance of this view in detection of orofacial clefts compared with the coronal view of retro nasal triangle and sagittal view of palatine line in the first trimester |
Zile-Velika (71) | 2023 | Observational study (retrospective cohort) | 18,759 births | Pregnant women in the first and second trimester of gestation | Latvia | Eur J Obstet Gynecol Reprod Biol X | To compare the ultrasound scan frequency and rate of congenital malformations between urban and rural areas |
†, diagnosis was established only at 14–16 weeks of gestation or later, if necessary (as reported in the manuscript). N/A, not applicable; NHS, National Health Service; FAP, fetal anomaly screening programme; FA, fetal anomaly; US, ultrasound; AUS, antenatal ultrasound; CL(P), cleft lip with or without cleft palate; CP, cleft palate; MRI, magnetic resonance imaging; OFCs, orofacial clefts; MTHSM, mandible transection head side shifting method; PRS, Pierre Robin sequence; RHSC, Royal Hospital for Sick Children; NBDPS, National Birth Defects Prevention Study; NT, nuchal translucency; 2D, two-dimensional.
Table 2
Study ID | Major findings | Detection rate reported | Main facial abnormality approached in the study |
---|---|---|---|
Aldridge 2023‡ (21) | Among 1,792 audited records, 221 cleft lip and palate abnormalities were detected before the FA scan, while 1,300 cases were detected through FA scans | For cleft lip, FA scan detection rate was 89.5% (95% CI: 87.8% to 90.9%), and antenatal up to 230/7 weeks detection rate was 90.9% (95% CI: 89.4% to 92.1%) | Facial clefts |
Bardi 2019§ (22) | The results from the evaluation of all the scans, 38.6% were dating scans and 61.4% were part of first-trimester screening. All cases of anencephaly (n=4), encephalocele (n=2), exomphalos (n=9), megacystis (n=4), and limb reduction (n=1) were diagnosed. First-trimester detection of gastroschisis and congenital heart defects was 67% and 19%, respectively. In the prenatal evaluation the anomalies were diagnosed in 200 (1.8%) fetuses; 81 (0.7%) were chromosomal and 119 (1.1%) were structural. The detection anomalies during prenatal exam, 27% (n=32) were observed at first-trimester scan, with a false-positive rate of 0.04% | From of all the exams carried out, the changes related to structural facial anomalies were cleft lip (1 case), cleft palate (1 case) cleft lip and palate (5 cases) | Facial abnormalities in general |
Bister 2011# (23) | Antenatal ultrasound screening could detect 17 out of 30 facial clefts. Sixteen of the 30 had isolated facial clefts. The incidence of facial clefts was 0.127% (95% CI: 0.089–0.182%); the incidence for isolated CLP was lower than previously reported: 0.067% (95% CI: 0.042–0.110%). For five patients, the US diagnosis of the type of facial clefting was not completely accurate and the correct diagnosis was established post-mortem. All five cases showed severe anomalies which lead to termination of pregnancy and a facial deformity was suspected. With one exception, all terminations were in fetuses with multiple anomalies. The figures presented will enable joint CLP clinics to give parents information of termination rates. The study allows pre-pregnancy counselling of families previously affected by clefting about the reliability of AUS detection rates | Overall, detection rate by AUS was 65% (67% isolated cleft lip, 93% CLP, and 22% isolated cleft palate), with no false positives | Facial clefts |
Bronshtein 2005# (24) | Glossoptosis with micrognathia was detected in 4 fetuses in the prospective group at 14- and 15-week of gestation. Both pregnancies were terminated; the diagnosis was confirmed in 1 case where postmortem examination was performed. There were no false-negative diagnoses in the other 7,998 fetuses. In all 4 cases, they were able to depict the glossoptosis and micrognathia on the US images, although these fetal scans were not performed exactly according to our methodology. All 4 fetuses had a normal karyotype and no other structural anomalies | 4 detected cases out of 80,000 pregnancies | Micrognathia, glossoptosis, and cleft palate |
Bronshtein 1998# (25) | All the women were at low risk for fetal malformations and except for three patients, all were younger than 35 years, without a family history of fetal malformations, exposure to teratogens, or consanguinity. In all but four cases, other fetal malformations were detected in addition to the nasal anomalies. The 15 nasal abnormalities included four cases of cebocephalus, three cases of proboscis, three cases of a flat nasal bridge, two cases of arrhinia, one case of a nasal tumor, a glioma, and one case of absent nasal septum. Women delivered normal neonates with a flat nasal bridge | Fifteen cases of fetal nasal abnormalities were diagnosed by ultrasound at 11–26 weeks’ gestation and most of them by TVS in the early second trimester. These 15 cases were detected out of 25,114 fetal sonographic examinations, giving a calculated prevalence of 1:1,676 cases (15 cases detected out of 25,114 cases) | Nasal malformations |
Bronshtein 1994# (26) | Eleven cases of fetal cleft lip with or without cleft palate were detected by transvaginal sonography among 14,988 fetuses (0.07%). In nine cases, no risk factors for cleft lip or palate existed. In six cases, the cleft lip represented an isolated malformation, with no other associated anomaly; in five of these six cases, the pregnancy was terminated. One additional case of a small cleft lip was not detected, for a false-negative rate of 8% | 11 detected cases out of 14,988 fetuses evaluated | Cleft lip or palate |
Cash 2001§,# (27) | Out of 23,577 live and still births, 30 had facial clefts; four were excluded from the study. Of the remaining 26 cases, 10 had associated major anomalies. There were 19 live births and seven terminations. Six of the seven terminations had other major abnormalities. Our detection rate for cleft lip and palate was 93% and the detection rate for isolated cleft palate was 22%. Isolated cleft lip was detected in 67% of cases. The overall detection rate for facial clefts was 65% | Sensitivity of 65% and a specificity of 100% for all facial clefts. Detection rate for cleft lip with or without palate (15/17 cases) was 88%. From the 23,577 cases, the negative predictive value was 99.9% (nine false-negative and 23,551 true-negative diagnoses) and a positive predictive value of 100% (no false positive and 17 true positive diagnoses) | Facial clefts |
Chelemen 2010§ (28) | The overall prevalence of major fetal structural abnormalities was 11.82%. There was an increase of incidence in later gestations: 6.82% in the first trimester; 44.82% in the second one and 48.30% in the third (out of which 19.31% were new cases). The highest incidence was noted for increased nuchal translucency and absent nasal bone in the first trimester (63.64%) and fetal growth restriction in the third trimester (37.16%) | The highest incidence was noted for increased nuchal translucency and absent nasal bone in the first trimester (63.64%) and fetal growth restriction in the third trimester (37.16%) | Structural abnormalities (nasal) |
Clementi 2000§,¶ (29) | A total of 709,027 births were covered; 7,758 cases with congenital malformations were registered. Included in the study were 751 cases reported with facial clefts: 553 CLP and 198 CP. One hundred pregnancies were terminated (13%); in 97 of these the cleft was associated with other malformations. Of the non-syndromic cases, 89 cases (16%) of the 533 were CLP and 38 cases (19%) of the 198 were CP | The prenatal diagnosis by transabdominal ultrasound of CLP was made in 65/366 cases with an isolated malformation, in 32/62 cases with chromosomal anomaly, in 30/89 cases with multiple malformations and in 21/36 syndromic cases. The prenatal diagnosis of CP was made in 13/198 cases | Cleft lip with or without cleft palate and cleft palate alone |
Gai 2022‡ (30) | 334 infants were identified with OFCs by either newborn physical exam or stillborn autopsy. In the current study, prenatal US diagnosed 287 fetuses with OFCs (30 cases of CLO, 254 cases of CLP, three cases of CPO), which included four false-positive cases who were misdiagnosed as with CLO (two cases) and CLP (two cases) and failed to detect 51 fetal OFCs (four cases of CLO, four cases of CLP, 43 cases of CPO). When we compared the predictive values between prenatal US and MRI, there were significant differences in the PPV of OFCs (P<0.05), NPV of OFCs (P<0.05), TPR of CLO (P<0.001), PPV of CLP (P<0.05), and TPR of CPO (P<0.05). Eventually, 86 mothers (88 fetuses, two sets of twins) decided to continue with the pregnancy and four mothers with multiple pregnancies chose selective fetus reduction, while 246 mothers chose to terminate the pregnancy | For detection of OFCs by US, the ACC, TPR, TNR, PPV, and NPV were 99.9% (110,286/111,178), 81.9% (230/281), 99.9% (109,948/110,005), 80.1% (230/287), and 99.9% (109,948/109,999), respectively | Orofacial clefts |
Hafner 1997# (31) | In 34 women in the 22nd week of gestation, the fetal facial region could not be observed sufficiently because of poor viewing conditions. These women were called back in week 28. In 21 of these patients, the fetal profile was either well or sufficiently seen at the second scan. Before the 34th week of pregnancy, two normal babies were born. The remaining 11 patients were examined again in week 34. Even at that time the facial region could only be viewed poorly in eight. All these babies were born without fetal malformations. Three of these eight pregnancies were terminated. None of them had termination prompted by facial malformation. Factors underlying the decision for termination were chromosomal abnormalities in one case, amniotic constriction band syndrome in one, and hydrocephaly in one case | Of the 5,407 women, 11 gave birth to babies with facial anomalies. Eight malformations were detected prenatally (72%). In the presence of associated anomalies, pre-natal ultrasound imaging to detect facial malformations showed 100 per cent sensitivity (five of five malformations were detected). In isolated facial malformations and particularly in those involving the lips, alveolus, and palate, the sensitivity was, however, much lower (only two of five malformations were detected) | Facial abnormalities in general |
Hegge 1986‡ (32) | There were seven abnormalities of the eyes, including three instances of absence of both eyes, two of hypertelorism, one of proptosis, and one of relative prominence. There were seven abnormalities of the nose, including three instances of marked flattening, one of absence, one of a proboscis, one of a single nostril, and one of a sunken appearance. There were two abnormally small chins. There was one marked cleft that involved the nose, lip, and palate. At least two fetuses with abnormal faces were missed entirely and coexistent facial abnormalities were missed in another three fetuses. Of the 11 fetuses with facial abnormalities identified, eight had other structural abnormalities as well, and the other three had either polyhydramnios or a history of teratogen exposure | The study identified 17 facial abnormalities in 11 fetuses (over the total 7,100 records) | Facial abnormalities in general |
Hjort-Pedersen 2023#,¶ (33) | All cases of anencephaly, diaphragmatic hernia, megacystis/urethral valves, omphalocele, and most cases of cleft lip, abdominal wall defects, clubfoot, and multiple malformations were detected. At the first-trimester ultrasound, none of the facial malformation was identified, while during the second-trimester ultrasound, 13 out of 17 was successfully identified (76.5%). Postnatal detection was performed in 3 cases | The prenatal DR of facial cleft malformations was 77% in the screening program, with a prevalence of 0.9 per 1,000. There were three (18%) false-negative cases with cleft lip and palate requiring treatment | Facial abnormalities in general |
Kelekci 2004§,# (34) | Among the group in which the NB was successfully evaluated, 54 pregnant women were evaluated by transvaginal ultrasound equipment. The NB was absent in 9 of the 594 unaffected cases (1.5%) and in 2 of the 6 affected cases (33.3%). Absence or presence of fetal NB, NT and CRL measurements, and the presence of ductus venosus reverse flow in A wave in both normal and abnormal. The prevalence of abnormal ductus venosus Doppler waveforms in normal pregnancies was 2% (95% CI: 1.02–6.76). Among the group with absent NB, there were 4 fetuses at 11–12 weeks of pregnancy (median CRL 56.4 mm), 3 fetuses at 12–13 weeks of pregnancy (median CRL 69.8 mm), and 4 fetuses at 13–14 weeks of pregnancy (median CRL 76.5 mm) | NB evaluation was successful in 600 of 642 (93.4%) ultrasound examinations. There were 594 unaffected and 6 affected fetuses: 2 DS cases and 4 cases having other pathological conditions (1 Turner’s syndrome, 1 hygroma colli, 1 trisomy 18, and 1 exomphalos) | Facial abnormalities in general (particular focus in nasal structures) |
Kong 2017# (35) | The authors diagnosed 119 cases with 154 congenital malformations (isolated: 82.35% cases; complex: 17.65% cases). The prenatal prevalence of congenital malformations was 54.38 for each 1,000 pregnancies, whereas the birth prevalence was 51.15 for each 1,000 births. The perinatal death rate was 35.29% (complex 73.68% and isolated 26.51%). The average maternal age of pregnant women was 29.94 years. Overall, the most widely observed congenital malformations involved circulatory system (20.78%), followed by musculoskeletal system (16.23%), followed by nervous system (12.34%), digestive system (7.79%), genital organs (6.49%), chromosomal abnormalities (5.84%), urinary system (4.55%), others (3.89%), and respiratory system (3.25%) | The prevalence of eye, ear, face, and neck anomalies were of 11.04%, while for cleft lip and cleft palate was of 7.79% | Facial abnormalities in general |
Lachmann 2018§,# (36) | The median CRL at the time of the first-trimester scan was 65 (range, 45–84) mm in the controls and 65 (range, 56–81) mm in the cases of isolated CLP. The diagnosis of CLP, which was isolated in all cases, was made at a median of 19 weeks’ gestation (range, 14–27 weeks of gestation). One patient who was classified at high risk for CLP at 11–13 weeks had the diagnosis confirmed and communicated at 27 weeks, because she missed 2 scheduled appointments (early anomaly scan at 16 weeks and anomaly scan at 22 weeks of gestation). In the control group, there was a significant increase with CRL in PMD (−0.29 + 0.11 × CRL in mm, SD 0.7041, P<0.0001, R2=0.686; Fig. 3). In the fetuses with isolated CLP, compared to the normal controls, the mean PMD was significantly decreased and it was below the 5th percentile of the reference range for CRL in 4 (80%) of the 5 cases | Fetuses with isolated CLP, compared to the normal controls, the mean PMD was significantly decreased and it was below the 5th percentile of the reference range for CRL in 4 (80%) of the 5 cases | Cleft lip and palate |
Lakshmy 2020# (37) | The superimposed line was absent in 17 fetuses with a cleft of the secondary palate that was confirmed by 3D evaluation. Of these, 13 had defects involving the premaxilla and four had an isolated cleft of the secondary palate. Postnatal confirmation was available in all cases. The sign was useful in ruling out cleft of the fetal secondary palate in 32 high-risk cases with a family history of cleft palate. The superimposed-line sign had a sensitivity of 89.5% in detecting cleft of the secondary palate | The superimposed-line sign had a sensitivity of 89.5% in detecting cleft of the secondary palate | Cleft of the fetal secondary palate |
Lakshmy 2017§ (38) | The suspicion was initially raised on 2D imaging, and in all 14 cases with positive markers, confirmation of the type and extent of the cleft was done by 3D evaluation. Visualization of 2D landmarks could be done in all, and 3D assessment was feasible in 94% of cases. Fourteen cases, of which 5 were unilateral, 4 bilateral, and 2 median cleft lip and palate, 2 median cleft palate, and 1 atypical palatine cleft were identified. There were no false-positives results reported, and 1 case of a bifid uvula was missed. Six of the volumes did not yield good results because of maternal obesity, as the overall image quality was poor. The salient features diagnostic of integrity of the palate on 2D imaging were an intact palatal line, continuity of the alveolar ridge, and complete base of the retronasal triangle. The soft tissue of the upper lip can also be assessed in all 3 planes for clefting, but the bony landmarks serve better in detecting clefts at this gestational age | Fourteen fetuses (over 2,014) with palatine clefts were identified during the study period | Palatine cleft |
Leiroz 2021# (39) | Prenatal ultrasound scans detected congenital abnormalities in 67 fetuses (6.9%) out of 967 pregnancies. The overall sensitivity and specificity of the mid-trimester ultrasound scan for congenital malformation detection were 61.1% and 96.3%, respectively, with an accuracy of 94.3% (P<0.05). According to the mid-trimester fetal ultrasound scan for the diagnosis of congenital anomalies, all 5 (0.53%) postnatal findings of myelomeningocele were previously diagnosed by mid-trimester fetal ultrasound scan | Regarding facial abnormalities, 2 patients with facial clefts were detected prenatally (2.9%) was detected prenatally, as well as 2 were detected postnatally (2.9%) | Cleft palate |
Li 2008‡ (40) | The incidence rate of fetal malformation was 22.5% in the study group. The detection rate of prenatal ultrasound was 79.02% (1,062/1,344) among which the detection rate of the severe malformation (87.58%, 860/982) were significantly higher than that of the minor malformation (55.80%, 202/362) (P<0.005). The false negative rate was high for the extremity malformations (39.46%) and facial malformations (31.91%), especially the acrosclerodermas, simple cleft palates, and ear deformities. Concluded that prenatal ultrasound is sensitive for severe fetal malformations, while detection rate is low for minor fetal malformations | Prenatal ultrasound detection sensitivity of facial abnormalities was 68.09%, with 160/235 true positives and 75/235 true negatives | Facial abnormalities in general |
Li 2023§ (41) | There were no false-positive results found. Three cases were missed but confirmed in the second-trimester anomaly scan, including 2 cases of isolated CP and one of isolated CL. Overall, the mandible transection head-side shifting method is feasible in assessing CLP at the time of routine first-trimester sonographic screening | Eighteen cases of CLP were identified in the first trimester. 9 (50.0%) were unilateral CLP, 4 (22.2%) were bilateral CLP, and 5 (27.8%) were median CLP. First-trimester diagnosis of CLP using MTHSM had a sensitivity of 85.7%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 99.9% | Cleft lip and palate |
Liao 2021§,# (42) | In general, 1,578 fetuses had at least one structural abnormality of the 53,349 total cases. The incidence of fetal structural malformations was about 3% (1,578/53,349) in this cohort. During first trimester screening we identified at least one abnormality in 680 out of the 1,578 pregnancies with a detection rate of 43.1% (95% CI: 40.6% to 45.5%). Anatomy scans during the 18 to 24 weeks period detected 488 (30.9%) abnormalities in 52,669 pregnancies. At the third trimester scan after 28 weeks, 112 (7.1%) abnormalities were detected in 52,181 pregnancies. Lastly, 298 (18.9%) abnormalities were observed in the remaining 52,069 live births by pediatricians during the neonatal period. The detection rate for several severe structural malformations during the first trimester were greater than 90% for anencephaly, exencephaly, cephalocele, and holoprosencephaly. This study highlights the value of first-trimester scanning using standardized sections for detecting fetal anomalies | Routine first trimester scans detected 30.8% of facial abnormalities. Among the 58 fetuses with holoprosencephaly, 49 had typical facial deformities. All facial deformities related to holoprosencephaly were identified | General fetal anomalies (congenital anomalies, face, and nervous system defects) |
Liao 2023# (43) | There is a typical “superimposed line” sign in the median sagittal section of the typically developing fetal face from 12 to 206/7 weeks of gestation. The PMD and hard palate transverse diameter of fetuses from 12 to 206/7 weeks of gestation increased linearly with time. The median sagittal section of the typically developing fetal face in the early stages of the second trimester presents a typical “superimposed line” sign, and the PMD and transverse palatal diameter increase with time. The four-step ultrasound screening method for fetal cleft lip and palate in the early stages of the second trimester has high clinical application value | Among 8,538 high-risk fetuses, 21 cases of cleft lip and palate were diagnosed by the four-step ultrasound screening method in the early stages of the second trimester | Cleft lip and palate |
Lind 2015‡ (44) | Visualization of a posterior cleft palate in addition to retro-micrognathia had a positive predictive value of 100% for PRS. The distribution of functional severity grades was similar in cases suspected prenatally as in 238 cases of PRS followed in the referral center in Necker Hospital. The majority of the identified fetuses (73%, 115/157) did not show a complete PRS but rather had other severe abnormalities. In these 115 cases, 77% resulted in pregnancy terminations, 9% in stillbirths, 3% in neonatal deaths and only 11% were live-born children. The most common finding was chromosomal aberrations (32%), unclassifiable polymalformative associations (24%), brain anomalies (23%) and skeletal anomalies (10%). Ten children (11%) had cranio-facial malformations with good neurological prognosis. There was no case of false positive of prenatal diagnosis of PRS in this group. The sensitivity of the jaw index is 100% and the specificity 98.7%. Once retrognathia is observed, a posterior CP must be searched | From a prenatal ultrasound database of 166,000 cases, 157 had one or more of the sonographic signs suggestive of PRS and had follow-up available. Of them, 33 (21%) had confirmed PRS, 9 (6%) were normal and 115 (73%) had chromosomal aberrations, associated malformations or neurological anomalies | Micrognathia/PRS, glossoptosis, and cleft palate |
Liu 2017§,# (45) | Among the 3,795 cases in this study, a total of 16 cases had CLP, with the incidence rate as 4.2%, including 13 cases of cleft lip and upper alveolar process or (and) palate, 81.2% (six cases were bilateral and six cases were unilateral), one case of central CLP, two cases of cleft lip alone, accounting for 12.5%, one case of cleft soft palate alone, accounting for 6.3%. Twelve cases were repeated ultrasonography at 17–18 GWs and in line with first-trimester diagnosis, all patients selected to terminate pregnancy, and all case were confirmed as cleft lip and upper alveolar process or (and) palate after abortion. The detection sensitivity and specificity of CLP in first-trimester were 75% and 100%, respectively, with positive predictive value of 100%, and negative predictive value of 99.8%. The detection rate of CLP in first trimester was 75%, with missed-diagnosis rate as 25% | First-trimester examination detected out 12 cases of cleft lip and alveolar process or (and) palate, with the detection rate as 75% (12/16); six cases were bilateral (one case was associated with nasal bone deficiency, and one case was associated with multiple malformations), the detection rate was 100% (6/6); five cases were unilateral (one case was associated with nasal bone deficiency), the detection rate was 80% (5/6), one case of median lip and palate (full fore-brain), the detection rate was 100% (1/1) | Cleft lip and palate |
Luedders 2011‡ (46) | During the study period, a total of 168/28,935 fetuses with an abnormal profile were identified. Retrospective reassessment of stored images using both objective measures (IFA and frontal nasomental angle) retrieved 54 eligible cases matching objective criteria of micrognathia, corresponding to an incidence of 1:536 in our cohort. The diagnosis of micrognathia has a crucial impact on both prenatal and postnatal outcomes of affected individuals due to its association with additional abnormalities | Fifty-eight cases (out of 168) had been subjectively interpreted as micrognathia during initial sonographic examination | Fetal micrognathia |
Maarse 2011# (47) | Sixty-two fetuses (liveborn, stillborn or TOP before 24 weeks) with confirmed orofacial clefts were identified in the study population. This resulted in a prevalence of 1.6 per 1,000 fetuses (including isolated and associated cases). For liveborn infants the prevalence in this group was 1.42. The distribution in the total population was 29% (18/62) CL, 40% (25/62) CLP, 27% (17/62) CP, one median cleft and one atypical cleft (4%). An additional five cases of facial cleft were identified postnatally by the cleft palate team in patients whose mothers had not undergone prenatal ultrasound screening. A total of 54 fetuses with clefts were in the low-risk population. There were 14 cases of CP, none of which was diagnosed prenatally. A total of eight fetuses with clefts were in the high-risk population. They all underwent at least two 2D and 3D second-trimester scans in the Wilhelmina Children’s Hospital. There were three cases of CP, none of which was diagnosed prenatally | CL was detected prenatally in 13/16 cases, giving a sensitivity of 81% (95% CI: 56–94%). For both low and high-risk patients, CL was detected prenatally in 2/2 cases and CLP was detected in 3/3 cases, giving a sensitivity of 100% (95% CI: 38–100%) | Facial clefts |
Merz 1997† (48) | Facial profile shown in the two-dimensional image represented the true mid-sagittal profile in only 69.6% of the cases. In the remaining 30.4%, the profile view deviated from a true mid-sagittal section by up to 20 degrees in one or two planes. In a total of 25 facial anomalies detected by abdominal ultrasound, 20 were clearly demonstrated by both two-dimensional and three-dimensional technology. In the remaining five cases, three-dimensional ultrasound revealed or confirmed an additional defect or abnormality: a narrow cleft lip in an unfavorable position of the fetal face (n=2), a unilateral orbital hypoplasia (n=1), a cranial ossification defect (n=1) and a flat profile in the presence of marked oligohydramnios (n=1). When transvaginal scanning was used, there were cases in which a detailed surface image of the fetal face could be obtained as early as 9 weeks’ gestation. Abdominal scanning routinely yielded high-quality surface images by 20 weeks. Three-dimensional ultrasound consistently displayed facial abnormalities with greater accuracy and clarity than conventional two-dimensional imaging | The three-dimensional orthogonal displays in 125 cases evaluated by abdominal ultrasound, the facial profile shown in the two-dimensional image represented the true mid-sagittal profile in 69.6% of the cases | Fetal face malformation |
Moreira 2023‡ (49) | In total, 672 patients with orofacial clefts born between: 40.9% CP, 38.1% CLP, 19.7% CL and 1.3% AC; 57.1% were male. CL, CLP, and AC were more frequent in male (64.2% and 55.6%, respectively), whereas CP was more identified in females (52.7%). Of patients born before 2001, 13.7% had a cleft diagnosed by ultrasound (34 patients of a total of 248 patients); of those born between 2001 and 2007, 32.6% had a prenatal diagnosis of orofacial clefts (44 patients of a total of 135 patients); and in those born after 2007, prenatal diagnosis increased to 47.1% (136 patients of a total of 289 patients). A statistically significant association was found for all pair wise differences (P<0.05) | The ultrasonography diagnosed 31.8% of patients. In total, a syndrome was recognized in 29% of patients. Since the implementation year of universal ultrasound screening in Portugal, 180 orofacial clefts were diagnosed in utero (vs. 34 before): 62.2% CLP, 27.2% CL, 10.0% CP and 0.6% AC | Facial clefts |
Offerdal 2008‡ (50) | The distribution of clefts was: 25 (25%) cleft lip, 52 (51%) cleft lip and palate, and 24 (24%) cleft palate. No cleft palate was detected prenatally. Median gestational time of detection of CLP was 19+2 (range, 10+3 to 40+4) weeks for the total period, with no change over time. Thirty-three of 77 (43%) with CLP and 14/24 (58%) with CP had associated anomalies. Twelve of 101 cases (12%) had chromosomal aberrations. In 18/101 (18%) the clefts were part of a syndrome/sequence | A total of 101 (n=49,314; incidence of 0.002%) fetuses or newborns with facial clefts were registered. CL(P) was detected prenatally in 35/77 (45%) of the cases, with a significant increase in the detection rate (P=0.03) from 14/41 (34%) to 21/36 (58%) between the two 9-year periods, respectively. Altogether 24/35 (69%) were detected at second-trimester routine ultrasound | Facial clefts |
Paaske 2018#,¶ (51) | There were no significant changes in prevalence over time for the two anomalies, calculated with and without inclusion of genetic and chromosomal cases. For isolated cleft lip with or without cleft palate none of the 157 cases born before 2005 were diagnosed prenatally compared to 34 of 58 cases (59%) born in 2005–2014 (P<0.01). The proportion of liveborn infants with multiple congenital anomalies also changed after 2005 with 15% (39/266) of all liveborn infants with orofacial clefts born 1980–2004 having multiple anomalies compared to 7% (7/96) in 2005–2014 (P<0.05). There was a statistically significant increase in the proportion of cases diagnosed prenatally (P<0.001). The increase was related to the prenatal diagnosis of CLP as the proportion of prenatal diagnosis of CP did not change. For isolated CLP none of the 157 cases born before 2005 were diagnosed prenatally compared to 34 of 58 cases (59%) born in 2005–2014. No cases with isolated CP were diagnosed prenatally. The proportion of liveborn infants with multiple congenital anomalies also changed since 2005 with 15% (39/266) of all liveborn cases with orofacial clefts born 1980–2004 having multiple anomalies compared to 7% (7/96) in 2005–2014 (P<0.05) | There were 271 cases diagnosed with cleft lip with or without cleft palate and 127 cases diagnosed with cleft palate, giving a prevalence of 14.8 per 10,000 births for cleft lip with or without cleft palate and 6.9 per 10,000 births for cleft palate. Overall, 66 cases were diagnosed prenatally (17% of total) | Orofacial clefts |
Paterson 2011‡ (52) | The value for CLP was markedly greater at 28% (65 of 236 cases). Of all cases, 51% were CLP. Although this value rose from 13% to 28% between 1999 and 2008, no statistically significant association with year of birth was noted (P=5.366). The percentage of CLP cases diagnosed prenatally rose from 11% to 50% between 1999 and 2008. A trend line was fitted to the graph via linear regression. The more extensive the cleft, the higher the percentage of cases that were diagnosed prenatally (P=0.048). This means that a significantly higher percentage of cases from the group of children with CLA or CLP (as opposed to CL on its own) were diagnosed prenatally. No significant link between associated abnormalities and a prenatal diagnosis of CLP was found (P=0.637). Thus, routine ultrasound anomaly scanning is shown to significantly improve detection rates compared with scanning of high-risk pregnancies only. Cases of CLP where the alveolus or the palate is involved have significantly higher detection rates than those involving only the lip | For the 459 cleft cases referred to RHSC over the 10-year study period, the overall percentage diagnosed prenatally was 15% (70 cases). CP on its own was diagnosed prenatally on only 5 of 223 occasions (2%); four of the five were associated with other abnormalities that may have accounted for the diagnosis | Facial clefts |
Pilalis 2012§,# (53) | A total of 3,902 pregnancies included 61 fetuses with structural defects (1.56%). Twenty-six (42.6%) were diagnosed in the first trimester and 29 (47.5%) in the second. Six anomalies were detected in the third trimester or after birth. Overall detection rate of the two-step program was 90.2%. The detection rates were 42.6% (26/61 anomalies) for the first trimester examination and 47.5% (29/61 anomalies) for the second trimester examination. The overall detection rate of the two-step screening program was 90.2%. Thus, detailed examination of fetal anatomy at 11 to 14 weeks resulted in the early diagnosis of about 40% of major structural defects | Out of 61 general defected detected in the study population, 3 cases of facial cleft were detected prenatally up to the second trimester of gestation, while 1 case of microphthalmia was detected up to the second trimester of gestation, and 1 case of hypoplastic ear was detected up to the 3rd trimester of gestation or postally | Major fetal structural defects |
Rabie 2019# (54) | During the study period—3,145 out of 3,404 ultrasounds were performed onsite, and 2,368 out of 2,499 performed remotely met the criteria for the study. The congenital anomaly prevalence in the on-site arm was 11.13%, while the teleultrasound arm had a prevalence of 5.66%. The sensitivity of on-site ultrasound was 76.57%, while for teleultrasound it was 57.46%. The specificity of on-site ultrasound was 92.77%, while for teleultrasound it was 98.21%. Using a non-inferiority limit of 0.15 with a 90% CI, the observed sensitivity difference was −0.1911; therefore, the sensitivity of teleultrasound is inferior to that of on-site ultrasound. Both accuracy and specificity of teleultrasound were not inferior to that of on-site ultrasound. The accuracy of on-site ultrasound was 90.97% while for teleultrasound it was 95.9% | Regarding midline abnormalities [including cleft lip, cleft palate and abdominal wall defects (other than gastroschisis and omphalocele)], false positive values for on-site ultrasound was 10 (out of 3,404—0.29%), while 8 (out of 2,499—0.32%) was observed in teleultrasound. On the other hand, false negative value for on-site ultrasound was 10 (out of 3,404—0.29%), compared to 7 (out of 2,499—0.28%) observed in teleultrasound | Major fetal structural defects |
Rodríguez Dehli 2010‡ (55) | Out of 145 oral clefts recorded, cleft lip was 26.9%, cleft lip and palate 28.3% and cleft palate 44.8%. Other associated defects were found in 18.6% of the total cases, with skeletal, cardiovascular and central nervous systems being the most common anomalies. Syndromes or sequences were found in 22% of clefts | Total prevalence of oral clefts was 14.4 per 10,000 births. A prenatal diagnosis was made in 12.4% | Orofacial clefts |
Rotten 2002#,¶ (56) | In normal fetuses, the inferior facial angle was constant over the time span studied. The mean (standard deviation) value of the inferior facial angle was 65.5 (8.13°). Consequently, an inferior facial angle value below 49.2° (mean; 2 standard deviations) defined as retrognathism. All the fetuses with syndromes associated with mandible pathology had inferior facial angle values below the cut-off value. The use of inferior facial angle and mandible width/maxilla width ratio should help sonographic recognition and characterization of fetal retrognathic and micrognathic mandibles in utero | Using 49.2° or the rounded-up value of 50° as a cut-off point, the inferior facial angle had a sensitivity of 1.0, a specificity of 0.989, a positive predictive value of 0.750 and a negative predictive value of 1.0 to predict retrognathia. | Retrognathia and micrognathia |
Shaikh 2022# (57) | A total of 270 children were born with cleft lip and/or palate, of which 130 had cleft lip with or without cleft palate. Only two diagnoses led to termination of the pregnancy. The severity of the cleft deformity was assessed by the operating surgeon and the results were compared with those from the prenatal scan. There were eight cases (38%) in which the severity of the prenatal diagnosis had been incorrect. Two lips were over diagnosed and two were under diagnosed. In one case, cleft lip was reported on the wrong side. Eight palates were either not visualized or under diagnosed. There was one case of gross under diagnosis: the child had bilateral facial and lateral clefts along with other abnormalities and died on the second day after delivery, active treatment having been withdrawn | Out of 270, 23 were positively diagnosed by the ultrasound scan. The specificity was 100% and the sensitivity was 17.5% | Orofacial clefts |
Stoll 2000† (58) | This study was done among 265,679 consecutive births covering 11 maternity hospitals from 1979–1998. The percentage of prenatal detection of CLP was low. CLP was detected rarely in the prenatal phase | For isolated malformation (fetuses with only CLP) the detection rate was low: 17.8%; however, this detection rate increased from 5.3% during the period 1979–1988 to 26.5% during the period 1989–1998, for fetuses with associated malformations (fetuses with CLP and one or more additional major malformations) these detection rates were 34.6%, 13.3% and 50.0%, respectively | Cleft lip and palate |
Suresh 2006# (59) | A total of 68 facial clefts were identified (0.2%). Twenty-nine cases of isolated facial clefts were diagnosed during the study period, of which 2 had unilateral cleft lip and 27 had unilateral cleft lip and palate. The PMT sign was absent in all cases of unilateral cleft lip and palate but was present in 2 cases of isolated cleft lip without cleft palate. The diagnosis of a facial cleft was missed in 3 cases referred before 24 weeks. In the 500 cases that were referred from the single hospital, there was no case of isolated unilateral cleft lip or cleft palate, and in all the cases, the PMT had been documented | The PMT sign can be easily incorporated into targeted sonography at 18 to 22 weeks’ gestation. Its inclusion would help in increasing the detection rate of unilateral cleft lip and palate. It may also be potentially used for differentiating between isolated cleft lip and cleft lip and palate, which helps in better prenatal counseling | Cleft lip and palate |
Syngelaki 2011§ (60) | Fetal abnormalities were observed in 488 (1.1%) of the remaining 44,859 cases; 213 (43.6%) of these were detected at 11–13 weeks. The early scan detected all cases of acrania, alobar holoprosencephaly, exomphalos, gastroschisis, megacystis and body stalk anomaly, 77% of absent hand or foot, 50% of diaphragmatic hernia, 50% of lethal skeletal dys, 60% of polydactyly, 34% of major cardiac defects, 5% of facial clefts and 14% of open spina bifida, but none of agenesis of the corpus callosum, cerebellar or vermian hypoplasia, echogenic lung lesions, bowel obstruction, most renal defects or talipes. NT was above the 95th percentile in 34% of fetuses with major cardiac defects. In 11 cases, the diagnosis of aneuploidy was made after 20 weeks. In these cases, the estimated risk for aneuploidies at first-trimester screening was low but amniocentesis was carried out because fetal defects were detected by the 20–24 weeks scan (n=10) or a third-trimester scan because of suspected fetal growth restriction (n=1) | The abnormalities were ventriculomegaly (n=2), hypoplasia of the vermis (n=2), facial cleft (n=3), and micrognathia (n=2) | Major fetal structural defects including facial anomalies |
Takita 2016§,# (61) | A total of 2,028 patients were enrolled in this study. Abnormal fetal morphological findings were found in the first trimester in 28 cases. Findings suggestive of fetal anomalies were observed in 24 cases in the first trimester. Twelve cases with ultrasound findings in the first trimester, including fetal edema, anencephaly, endocardial cushion defect, exhibited an abnormal chromosome after amniocentesis. Ultrasound findings in the first trimester disappeared until 18 weeks of gestation in eight cases, and they were preserved in three cases. Fetal anomalies were primarily noted in the second trimester in 10 cases. However, after delivery, morphological abnormalities were primarily observed in 18 cases. Visualized rates for each ultrasound finding in the first trimester were as follows: skull and brain 99.8% and face 99.8% | Three cases of cleft lip had a prenatal diagnosis (out of 28 – 10.7%). In addition, among the 28 abnormalities detected, 2 cases of anencephaly were detected prenatally. Fetal anomalies were primarily noted in the second trimester in 10 cases, including three cases of cleft lip. | General fetal anomalies |
Tang 2012§,# (62) | Missed diagnosis occurred in 9 fetuses, including 3 of cleft lip, 1 of chilopalatognathus, 5 of external ear shape or size abnormality. All of the fetuses were confirmed with induced or postnatal follow-up | Totally 11 fetuses of face malformations or suspected abnormality were diagnosed with ultrasound, including 1 narrow eye distance, 5 absence or unclear nasal bone, 3 unclear upper jaw and 2 cheilopalatognathus | Fetus face malformations |
Trout 1994#,¶ (63) | Sonograms and autopsy and clinical data from six cases of hypotelorism, two of cyclopia, and three of hypertelorism were reviewed retrospectively. Both inner and outer orbital measurements fell clearly below two standard deviations of the mean in all six cases of hypotelorism. The three cases of hypertelorism had inner orbital measurements above the 95th percentile and outer orbital distances within normal limits but near the 95th percentile. All cases with abnormal orbital distances had associated intra- or extracranial abnormalities, including holoprosencephaly, encephalocele, and cleft palate. Extracranial anomalies identified included cleft palate, choanal atresia, and ventral wall defect. Inner orbital measurement was more representative of dysmorphology, as compared to outer measurement of the orbit | Six cases had hypotelorism, three—hypertelorism, cyclopia—two cases | Orbital anomalies and cleft palate |
Vial 2001 (64) | A total of 1,270 fetal malformations were compared with 38,110 births with a prevalence of 3.3%. The lowest detection rate was observed for cardiac anomalies, with only 23% correct diagnoses. The tertiary center achieved an 88% (7/8) detection rate in its outpatient clinic and 83% in referred patients. Outside the referral center, the diagnostic rate attained 41% (14/34). Awareness of screening performance in the general population provides evidence to explain the limits of ultrasonographic examination and emphasizes the need for a network of trained ultrasonographers | Facial cleft was present in 42 fetuses. The overall sensitivity to identify facial clefts was 50%. Global sensitivity was 54.5% | Facial cleft |
Wayne 2002# (65) | A total of 17,551 patients underwent routine detailed anomaly scans between 18 and 23 weeks of gestation. Tangential and transverse views were used. Prevalence of isolated facial clefts: During the study period 22 facial clefts (12 isolated) were identified, making the overall prevalence 1.3 in 1,000 (0.13%) infants and the prevalence of isolated clefts 1 in 1,500 (0.07%) infants. Sensitivity of routine antenatal screening: antenatal diagnosis was found to be inaccurate in five cases giving an accuracy of 80.7%. There were no false positive diagnoses of facial clefts | In the routinely screened population, 12 neonates underwent surgery for facial clefts. Nine of these clefts (75%) were identified in the antenatal period. Of the three facial clefts missed on routine antenatal ultrasound, all were unilateral: one a small incomplete cleft of the vermilion, one an isolated cleft palate and the third a cleft of the lip and palate. Accuracy of antenatal ultrasound: during the study period, 30 neonates (12 local, 18 referred) underwent surgery for facial cleft. Of these, 26 neonates had an antenatal diagnosis and detailed assessment of the facial cleft | Facial clefts |
Weedn 2014#,¶ (66) | Among the 4,013 women, 1,829 (46%) reported that they had an abnormal ultrasound result; 73% to 83% carrying a fetus with isolated omphalocele, anencephaly, gastroschisis, and renal agenesis reported having an abnormal ultrasound result compared with 15% to 28% carrying a fetus with an isolated cleft palate, cleft lip with or without palate, or limb deficiency. Overall, 71% of the participants who carried a fetus with a birth defect reported that their initial abnormal ultrasound result was in the second trimester. Differences in reports of an abnormal ultrasound result based on maternal characteristics were significant for maternal race/ethnicity and body mass index. The Hispanic women were 20% less likely to report an abnormal ultrasound result than the white women (OR =0.78; 95% CI: 0.65–0.94). The women with a BMI of 30 kg/m2 or greater were less likely to report an abnormal ultrasound result than those with a normal BMI (OR =0.83; 95% CI: 0.70–0.99). As expected, most participants who carried fetuses with more than one birth defect were more likely to report an abnormal ultrasound than participants who carried fetuses with isolated birth defects (51% vs. 45%, P=0.0028), most notable for those affected with cleft palate (36% vs. 15%, P<0.001) and limb deficiencies (50% vs. 26%, P<0.001) | In total, cleft palate was observed in 486 patients (19.6% being reported as abnormal in the ultrasound), while cleft lip was observed in 1,011 patients (with 30.1% being reported in an ultrasound) | Cleft palate, cleft lip with or without cleft palate |
Weiner 2007# (67) | Out of the 1,723 NT examinations, transabdominal approach was used in 85% of the scans. Further evaluation of these cases diagnosed 9 fetuses (0.52%) with structural anomalies including: acrania, holoprosencephaly, Dandy Walker syndrome, cerebellar agenesis, prune belly syndrome, 2 cases of omphalocele, and 2 cases of cleft lip. The NT was abnormal (greater than 3 mm) in only 1 case (omphalocele). None of the additional 8 cases diagnosed with structural anomalies had a positive maternal serum screening result for trisomy 21. Eight of these 9 fetal structural anomalies were confirmed using an ultrasound at 14 to 16 weeks of gestation and the remaining 1 was confirmed at 20 weeks of gestation | The sonographers suspected structural fetal anomalies in 22 cases (1.3%), performed between 11.2 to 13 weeks of gestation. Four cases of cleft palate and cleft lip was suspected during NT examination and confirmed anatomically | Structural fetal anomalies, cleft and lip palate |
Wilhelm 2010#,¶ (68) | In 90.7% of the cases (605/667) the uvula could be detected as a typical ‘equals sign’. Visualization of the soft palate in the median sagittal section was successful in 85.3% of the cases (569/667). Detection of at least one of the two structures (either the uvula in a frontal section or the soft palate in a sagittal section) was successful in 98.4% (656/667) of cases. We found three cases with clefts in our patient series. In one case, in which neither the uvula nor the soft palate could be visualized, a CP was diagnosed and confirmed after birth. Either because of the general ultrasound conditions or the unfavorable position of the fetus (significant flexion of the head), in eight cases (1.2%) it was impossible to visualize either the uvula or the soft palate. Therefore, the integrity of the palate could not be assessed. | A normal uvula could be visualized with a typical echo pattern (the ‘equals sign’) in 90.7% of the cases and the soft palate could be completely visualized in a median sagittal section in 85.3% of the cases. Visualization of at least one of the two structures (either the uvula or the soft palate) was successful in 98.4% of the cases. In one case an isolated cleft palate (in an otherwise normal fetus) was diagnosed; in one case with a cleft lip and palate, the cleft palate and the completely split uvula were detected. In 1.2% of the cases the examination did not provide sufficient information on either the uvula or the soft palate | Cleft palate |
Zhen 2021§,# (69) | The medial maternal age was 29 years (21 to 40 years), and the median gestational age at which the diagnosis was made by ultrasound was 12 weeks (range, 11–14 weeks). Four cases—declined invasive testing or lost to follow up. Twenty-three cases refused WES; among them additional anomalies were found in 10 cases. The decision to terminate pregnancy was made in 25 cases. Thirteen were confirmed to have PRS, respiratory difficulties occurred in 76.9% (10 out of 13) | Out of the 19,800 NT scans, 47 cases of isolated fetal micrognathia were diagnosed during antenatal screening. Forty-three cases identified in the first trimester as micrognathia, proceeded with genetic testing and follow-up ultrasounds. In the second trimester ultrasound, 5 out of 13 still showed isolated micrognathia with one case with a positive WES result (all 5 cases did not have a detected pathologic variant) | Fetal micrognathia |
Zheng 2018# (70) | A total of 2,879 fetuses (including 302 twins) were included in the study. Three of the five bilateral CLP and two out of three unilateral CLP were associated with other structural anomalies like congenital heart disease, omphalocele, pericardial effusion and gastroschisis. Satisfactory axial view of maxilla, sagittal view of palate, and coronal view of RNT with 2-dimensional ultrasound was rated as 95.2% (2,740/2,879), 98.2% (2,827/2,879) and 93.8% (2,700/2,879) respectively. The study demonstrates that using the axial view of maxilla in the diagnosis of OFC is feasible and improved the detection of OFC compared with the sagittal view of the palatine line and coronal view of the RNT in the first trimester | Eight cases of OFC were diagnosed in the first trimester including three unilateral and five bilateral cleft palate and no additional cases observed in the post-natal evaluations. Detection of CLP with abnormal image of the maxilla in axial view, RNT in coronal view, palatine line in sagittal view in the first trimester had a sensitivity of 100%, 75%, and 50%, respectively | Orofacial clefts |
Zile-Velika 2023§,# (71) | Among the 18,759 infants born during the study period, 536 had birth defects (prevalence rate of 28.6 per 1,000 births). Proportion of congenital anomalies were higher in the capital city as compared to rural areas and other big cities. Deformations of the musculoskeletal system, congenital malformations of circulatory, genital, urinary, and digestive systems were the top five congenital anomalies at birth. Higher number of ultrasound scans were observed in the rural areas, though there were some regional variations in the frequency of specific congenital anomalies | The congenital malformations of the eye, ear, face and neck accounted for 3% (n=17), and cleft lip along with cleft palate accounted for 4% (n=21) | Cleft lip and cleft palate and general congenital malformations |
§, gestational age of assessment—first semester; #, gestational age of assessment—second semester; ¶, gestational age of assessment—third semester; †, gestational age of assessment—all semesters; ‡, gestational age of assessment—not reported. FA, fetal anomaly; CI, confidence interval; CLP, cleft lip and palate; US, ultrasound; AUS, antenatal ultrasound; TVS, transvaginal ultrasound; CP, cleft palate; OFCs, orofacial clefts; CLO, cleft lip only; CPO, cleft palate only; MRI, magnetic resonance imaging; PPV, positive predictive value; NPV, negative predictive value; TPR, true positive rate; ACC, total accuracy; TNR, true negative rate; DR, detection rate; NB, nasal bone; CRL, crown-rump length; DS, Down’s syndrome; PMD, palatino-maxillary diameter; SD, standard deviation; 2D, two-dimensional; CL, cleft lip; MTHSM, mandible transection head-side shifting method; PRS, Pierre Robin sequence; GWs, gestational weeks; IFA, inferior facial angle; TOP, termination of pregnancy; AC, atypical cleft; CLA, cleft lip and alveolus; RHSC, Royal Hospital for Sick Children; PMT, premaxillary triangle; OR, odds ratio; BMI, body mass index; WES, whole-exome sequencing; RNT, retronasal triangle.
Table 3
Author | Cleft (L + P) or general facial cleft | Cleft (P) | Cleft (L) | Micrognathia | Glossoptosis | Retrognathia | Nasal bone | Upper jaw | Orbital | Uvula |
---|---|---|---|---|---|---|---|---|---|---|
Aldridge 2023 (21) | × | × | ||||||||
Bardi 2019 (22) | × | × | × | |||||||
Bister 2011 (23) | × | × | × | |||||||
Bronshtein 2005 (24) | × | × | ||||||||
Bronshtein 1998 (25) | × | |||||||||
Bronshtein 1994 (26) | × | × | ||||||||
Cash 2001 (27) | × | × | × | |||||||
Chelemen 2010 (28) | × | |||||||||
Clementi 2000 (29) | × | × | × | |||||||
Gai 2022 (30) | × | × | × | |||||||
Hafner 1997 (31) | × | |||||||||
Hegge 1986 (62) | × | × | × | × | × | |||||
Hjort-Pedersen 2023 (33) | × | × | × | |||||||
Kelekci 2004 (34) | × | × | ||||||||
Kong 2017 (35) | × | × | × | × | ||||||
Lachmann 2018 (36) | × | × | ||||||||
Lakshmy 2020 (37) | × | |||||||||
Lakshmy 2017 (38) | × | |||||||||
Leiroz 2021 (39) | × | × | ||||||||
Li 2008 (40) | × | × | ||||||||
Li 2023 (41) | × | × | × | |||||||
Liao 2021 (42) | × | × | × | × | × | |||||
Liao 2023 (43) | × | × | ||||||||
Lind 2015 (44) | × | × | × | |||||||
Liu 2017 (45) | × | × | ||||||||
Luedders 2011 (46) | × | |||||||||
Maarse 2011 (47) | × | × | × | |||||||
Merz 1997 (48) | × | |||||||||
Moreira 2023 (49) | × | × | × | |||||||
Offerdal 2008 (50) | × | × | × | |||||||
Paaske 2018 (51) | × | × | × | |||||||
Paterson 2011 (52) | × | × | × | |||||||
Pilalis 2012 (53) | × | |||||||||
Rabie 2019 (54) | × | × | ||||||||
Rodríguez Dehli 2010 (55) | × | × | × | |||||||
Rotten 2002 (56) | × | × | ||||||||
Shaikh 2022 (57) | × | × | × | |||||||
Stoll 2000 (58) | × | |||||||||
Suresh 2006 (59) | × | × | × | |||||||
Syngelaki 2011 (60) | × | × | ||||||||
Takita 2016 (61) | × | × | ||||||||
Tang 2012 (62) | × | × | ||||||||
Trout 1994 (63) | × | × | × | |||||||
Vial 2001 (64) | × | |||||||||
Wayne 2002 (65) | × | × | × | |||||||
Weedn 2014 (66) | × | × | × | |||||||
Weiner 2007 (67) | × | × | × | |||||||
Wilhelm 2010 (68) | × | × | ||||||||
Zhen 2021 (69) | × | |||||||||
Zheng 2018 (70) | × | × | × | |||||||
Zile-Velika 2023 (71) | × | × | × | |||||||
Total | 34 | 36 | 30 | 7 | 2 | 1 | 6 | 1 | 3 | 1 |
The × symbols represent that that particular pathology was mentioned within that particularly study. L, lip; P, palate.
Results
Main characteristics of included primary studies
Figure 1 illustrates the PRISMA-ScR flowchart detailing the scoping review’s search approach. Initially, 3,672 studies were obtained from the search and reference list. Among these, 242 were identified and removed as duplicates. Subsequently, after scrutinizing the titles and abstracts of the remaining studies, 3,292 were excluded due to a failure of meeting the inclusion criteria. Upon thorough examination of the full texts of the remaining 138 studies, 87 were disqualified, as they also did not fulfill the inclusion criteria. Ultimately, 51 studies met the eligibility criteria and were included in the review for further in-depth analysis (Tables 1,2).
The main characteristics of the included studies are presented in Table 1. Among the 51 eligible studies, the two oldest studies were published in 1986 (32) and 1997 (31)—two prospective trials on the incidence of facial abnormalities identified during routine screening. Six studies were published in 2023 (21,33,41,43,49,71), mostly investigating the performance of multiple-trimester US techniques in detecting in-uterus oral-related malformations. Geographically, 10 studies were carried out in China (30,35,40-43,45,62,69,70), and five in the USA (32,54,63,66,67). The remaining studies were conducted in various countries worldwide, including the UK (21,23,27-29,52,57,60,65) (n=9), France (29,44,56,58), Germany (29,36,46,48) and Israel (24-26,67) (n=4), Denmark (29,33,51) (n=3), India (37,38) and Austria (29,31) (n=2). These studies primarily focused on pregnant women in general or under high-risk gestations, either in the first, second, or third gestational trimester. Interestingly, some studies reported the number of evaluated patients, not reporting the number of pregnant individuals a priori. Among the reported studies, our scoping review encompasses data from 614,245 pregnancies, 680,986 fetuses or births, and 376,300 US examinations. Various assessment tools were used to evaluate the fetus’ morphology among enrolled women. Regular US images were performed evaluating 2 dimensions, while a small minority used more advanced techniques (3-dimensional ultrasonography).
Commonly reported skull types and orofacial abnormalities
The full description of the most frequently reported skull types and orofacial abnormalities among the included studies is presented in Tables 2,3. Our study identified a wide range of oro- and craniofacial abnormalities that might be diagnosed using routine GUS assessment. Most importantly, facial clefts or variations thereof (i.e., cleft lip, cleft palate, and orofacial clefts) were the most reported facial malformations detected via gestational imaging. Specifically, facial clefts in general and cleft lip associated with cleft palate were the second most frequently observed malformation reported among included studies (n=34; 66.7%) (21,23,24,32,38,39,41-45,47,52-54,58,61,63-67,70,71). We additionally collected data associated with micrognathia (26,42,44,46,56,60,69), associated with or without glossoptosis and cleft palate. Within these studies, authors mainly emphasized the impact of the malformations on breathing and feeding outcomes in neonates. Only one study reported data on orbital anomalies (63).
Detection rate and performance metrics reported within included primary studies
We observed extreme variability in the described performance values derived from the respective utilized techniques, with some studies reporting prevalence rates, while other studies provided more robust evaluations including sensitivity, specificity, and predictive positive and negative values. The identified metric values differentiated based on certain characteristics, including type of malformation, the gestational age by the time of screening, as well as the presence of underlying anomalies (multiple abnormalities). For instance, as far as cleft lip and palate detection rates are concerned, the report provided by Aldridge et al. suggested detection rates of fetal anomalies reaching 89.5% (95% CI: 87.8% to 90.9%), while antenatal up to 230/7 weeks detection rate was 90.9% (95% CI: 89.4% to 92.1%) (21) Likewise, as evidence in Bister and colleagues (23), the overall detection rate by AUS of facial clefts was 65% (particularly of 67% isolated cleft lip, 93% cleft lip and palate, and 22% isolated cleft palate), without any false positives. Additionally, based on the results emphasized in the study of Hjort-Pedersen et al. (33), all cases of cleft lip and multiple malformations were detected via prenatal screening, with no facial malformations being detected during the initial first trimester US. However, in the subsequent second-trimester US, 13 out of 17 malformations were successfully identified, constituting a 76.5% success rate (33). Notably, the detection rates differed significantly according to the type of facial malformation that was primarily identified. Some malformations, such as micrognathia, were detected in a significant number of patients through routine US evaluations, while others, such as facial clefts, showed high variation in sensitivity rates (24,70). Some studies reported data associated with accuracy performance metrics of US findings in detecting orofacial anomalies. For instance, as evidence in Gai et al. (30), the detection of orofacial clefts through AUS presented high performance values, with the total accuracy, true positive rate, true negative rate, positive predictive value, and negative predictive value of 99.9% (110,286/111,178), 81.9% (230/281), 99.9% (109,948/110,005), 80.1% (230/287), and 99.9% (109,948/109,999), respectively. Similarly, as proposed by Hafner et al. (31), based on a study conducted to shed light on the incidence of facial malformations, prenatal detection rate, and on the clinical implications of their detection, prenatal US had a sensitivity of 100%. In isolated facial malformations and particularly those involving the lips, alveolus, and palate, the sensitivity was, however, much lower (only two of five malformations were detected) (31). Lastly, Li et al. (40), after evaluating a Chinese cohort to evaluate the value of the prenatal US in the diagnosis of fetal malformation, observed that the prenatal US detection sensitivity of facial abnormalities was 68.09%, with 160/235 true positives, and 75/235 true negatives. Severe structural malformations were reported as associated with elevated sensitivity rates. According to the results demonstrated by Liao et al. (42,43) and Li et al. (40), first trimester detection rate of some facial abnormalities such as anencephaly, exencephaly, cephalocele, and holoprosencephaly reached sensitivity performance of 90%.
Interestingly, one report included in our review demonstrated an increase in detection rates of isolated oral malformations over time. As suggested in French results from Stoll et al., there was an improvement in detection rates from the period between 1979–1988 compared to 1989–1998 (5.3% to 26.5%, respectively) (58). We calculated the incidence of some diseases registered within included studies. Overall, the incidence rates of anomalies were considerably low, typically lower than 4% (as registered in the study of Liu et al.) (45). In general, the calculated incidence values ranged from 0.067% (25) to 22.5% (40), which varied based on the sample size enrolled in each trial. Even though the reported abnormalities are associated with low incidence rates, most studies still reported elevated accuracy performance metrics (such as sensitivity and specificity). For instance, Bronshtein et al. (24) evidenced that among the two cases of anomalies out of the 8,000 cases, both cases were detected through AUS, with no false negative results. This can be translated as clear evidence of GUS’s applicability and effectiveness in early detecting oro- and craniofacial anomalies during the in-uterus stage.
To note, the presence of multiple anomalies increased the detection rates of the registered anomalies. For example, GUS was shown to have a 100% sensitivity in the presence of multiple abnormalities such as reported by Luedders et al. (46). However, as the sample sizes of positive cases is considered to be limited, definite and conclusive statements might be taken carefully. Another detection modulator reported within included studies associations among the type of US technique employed during routine analyses. Primary studies’ findings showed that specialized US techniques or multi-step screening programs are more effective in detecting oro- and craniofacial conditions in early stages, specifically in high-risk pregnancies. For instance, the results provided by Liao et al. evidenced that from the 8,538 high-risk fetuses, 21 cases of cleft lip and palate were diagnosed by the four-step US screening method in the early stages of the second trimester (43). The authors defined the four-step evaluation based on the assessment of (I) median sagittal; (II) oblique coronal section of the posterior nasal triangle; (III) transverse section of the alveolar process of the maxilla; and (IV) cross-section of the horizontal plate of the palate. Lastly, we observed that the gestational age might also modulate the detection rates of facial and neck anomalies. For instance, some studies suggested benefits and high detection rates for certain conditions (i.e., cleft and lip palate) when imaging were performed and obtained in the first trimester (41,61,70).
Healthcare implications of early detection of cranio- and orofacial malformations
The healthcare-related implications originated by the performance of AUS was not widely reported among included primary studies. To note, pregnancy termination was the only medical and social implications registered among the identified trials (23,31,44,47,72). For instance, following the evaluation of more than 7,900 fetuses, Bronshtein et al. (24) stressed the fact that all cases (four pregnancies) in which glossoptosis and micrognathia were identified through in utero scanning coursed with birth termination.
Moreover, as reported in 1997 by Hafner et al. (31), prenatal screening identified eight malformations (72%) before birth, and among these cases, three pregnancies were terminated. In the study carried out by Hafner et al. (31), termination in these instances was not prompted by the facial malformation itself but based on factors such as chromosomal abnormalities in one case, amniotic constriction band syndrome in another, and hydrocephaly in a third case.
Technical limitations of performing US
Our research team rarely found information of potential technique limitations that might have hindered the execution of AUS in the included clinical trials. To note, Lakshmy et al. (38) reported barriers and difficulties facing while performing GUS and their potential implications for pathology detection. As evidenced in the publication, 14 cases involving palatine clefts in fetuses were identified during the study period (38). Initially, suspicion arose from 2-dimensional imaging, and in all 14 cases where positive markers were present, confirmation of the cleft abnormalities type and extent was achieved only through 3-dimensional evaluation (38). However, six volumes yielded unsatisfactory results due to maternal obesity, leading to poor overall image quality (38). Additionally, as stressed by Vial et al. (64) [2001], the training of healthcare professionals (potential technical and personnel limitations) involved in AUS is essential to guarantee high-performance.
Discussion
Our scoping review of the utilization of AUS evaluations targeting the identification of oro- and craniofacial abnormalities showed the effectiveness of this technique for multiple diseases, including orofacial clefts, facial and neck abnormalities, micrognathia, and glossoptosis, with relatively high-performance rates. In addition, we evidenced, based on a limited number of clinical trials, that the detection of certain orofacial conditions (i.e., cleft lip and palate) can be associated with relatively high sensitivity and accuracy values. Notably, we observed that the detection performance might vary based on the type of abnormality presented by the fetuses, the presence of coexisting anomalies, and the timing and/or method utilized for the US evaluation. Moreover, the collated evidence demonstrates that the performance of routine GUS and the early detection of morphological US might have direct implications on maternal decisions of pregnancy termination.
As reported in our study, facial clefts, palate deformities, micrognathia, and glossoptosis can be detected through antenatal screening, in multiple gestational stages. Although not systematically advocated by international health authorities and expert groups (73), the potential of AUS to detect a complex range of oro- and craniofacial abnormalities is both robust and promising. For example, the evaluation of tongue positioning (74,75), the assessment of the functional suctioning pattern (76,77), the appraisal tongue’s movements while suctioning the amniotic liquid or fingers (78,79), and the recognition of certain facial profile patterns (80) (i.e., retrognathic or prognathic patterns besides micrognathia or macrognathia) could complement the existing guidelines of best practice. It is worth mentioning that the tongue plays a very important role in stomatognathic development (81). As such, changes in stomatognathic system (particularly involving soft tissues and the palate) could already be observed in-uterus if ultrasonographers are “aware” and “sensibilized” of the facial structures that can be examined in both coronally and axially oriented sequences. Anomalies in tongue development and function, such as observed in patients with ankyloglossia, could affect breastfeeding, the development of the maxillary arch, and prompt future speech disorders, malocclusion, and gingival recession (82,83). Therefore, there is an important call for action from our research team “to expand the existing plan of facial structures to be examined during routine antenatal ultrasonography”.
Unlike the findings identified in our review, the body of literature discussing the barriers for evaluating the gestational ultrasonography images is currently vast and solid. First, some studies have suggested that the prenatal assessment of other structures rather than the currently prioritized by international societies might be time-consuming and with limited standardized and validated protocols (84). Nevertheless, methodology-focused trials, such as the one proposed by Macé et al. (84), demonstrated that technical validation of additional parameters of assessment is feasible, viable, and not burdensome (84). By describing the combination of a coronal view of the pharynx of the fetal upper airway, the authors suggested a new approach that might be useful to easily assess glossoptosis in fetuses (84). In addition, issues associated with quality assurance, technical or infrastructure limitations (especially in low- and middle-income countries), as well as maintenance and service or product supply are also important difficulties emphasized in the literature (85). Additionally, healthcare professionals’ (e.g., sonographers and technicians) willingness to receive constant and updated trainings hinders the applicability of new structures to be further evaluated during routine screenings (86,87). The highlighted barriers can be promptly overcome with adequate procurement and strong supply chain initiatives, the strengthening of healthcare governance, and the establishment of appropriate health policies. In addition, the analyses of multiple and more complex parameters derived from routine antenatal ultrasonography must be operationalized based on interdisciplinary collaboration and collective thinking. The collaboration among different healthcare experts, including dental specialists, gynecologists and obstetricians, fetal medicine physicians, and otorhinolaryngologists are essential and cannot be overstated. The timely diagnosis and intervention are crucial, particularly in growing children, to manage these conditions both effectively and promptly.
Over the past several years, dental specialists from across the globe have started encouraging healthcare providers to “early-timely-diagnose dental-related disorders”. Based on a systematic review published by Valério et al. following a timely diagnosis of malocclusion, the subsequential early treatment of these pathologies was shown to improve facial asymmetry, particularly in the lower part of the face, along with an increase in palatal volume and palatal surface (88). Additionally, the authors’ findings suggest that the benefits generated by early orthodontic interventions are associated with the improvement of craniofacial symmetry/bone structure, and a refinement in masticatory ability and performance (88). Regarding prenatal assessment using US, Chedid et al. suggested that this exam can be introduced in pediatric dentistry as a diagnostic tool to identify the risk of malocclusion, and during pregnancy dental care as a mode of education and motivational guidance for breastfeeding and healthy habits for parents (89). Similarly, different studies have highlighted the benefits of early detection of oral neoplasms, as they offer an effective mode of reducing the individual burden of disease, decreasing morbidity and mortality, and improving overall quality of life (90,91). Thus, by calling attention to the underused potential of routine GUS techniques, our study also endorses the aforementioned concept of timely diagnosis associated with orofacial disorders that can be verified while in utero, as this practice can significantly reduce short- and long-term dysfunctionality and improve both self-esteem and overall quality of life.
With the advancement and rapid improvement of healthcare technologies, 3- and 4-dimensional GUS and multiple digital technologies have become progressively more common in routine practice (91). The potential applicability of 3- and 4-dimensional GUS in dental care relies on their capability to review volume data interactively, utilize various section planes for assessing anatomical structures beyond the original acquisition plane, and rotate the volume dataset in order to facilitate examination of anatomical structures from diverse perspectives (91). In addition, 3D and 4D GUS can access a range of rendering methods. This enables examiners to visualize different characteristics of a single structure (for instance, revealing the external aspect of a meningomyelocele when rendered in surface mode or displaying underlying bones in the maximum-intensity mode using the same fetal back volume dataset). With regards to existing digital health technologies, their potential is even broader. For instance, machine learning and deep learning algorithms can efficiently evaluate GUS images, identifying several abnormalities and anomalies in fetuses (91). By using a wide spectrum of deep learning models [such as convolutional neural networks (CNNs), recurrent neural networks (RNNs), and others], these techniques have been able to increase the detection of different types of congenital abnormalities, including head and neck malformation, heart defects, pulmonary and renal diseases (91). They not only increase health-related outcomes on maternal and child health, but also support obstetricians and radiologists screen for problems and intervene early to improve fetal outcomes (91). Further, the application of artificial intelligence and machine learning algorithms in fetal ultrasonic disease diagnosis has become a reality, yet mostly within private practices and high-income countries. Artificial intelligence plays a supporting role in the identification of fetal facial features, craniofacial development, and the detection of congenital abnormalities. As proposed by Zhen et al., the utilization of the deep CNN method facilitated the automatic recognition of axial, coronal, and sagittal planes within the facial structure, significantly reducing section recognition time with an efficiency of 96.99% (92). In another publication by Tsai et al., image registration technology was employed to standardize fetal position, orientation, and size variations by pinpointing specific head and eye areas as reference points (93). Following this, craniofacial structures were automatically outlined using segmentation techniques, allowing for the precise measurement of five craniofacial diameter lines (biparietal diameter, occipitofrontal diameter, interorbital diameter, bilateral orbital diameter, and orbital-calvaria diameter) (93). This approach facilitated the diagnostic assessment of fetal facial characteristics. Apart from evaluating facial growth and abnormalities, artificial intelligence offers enhanced diagnostic effectivity by preprocessing US images, eliminating facial obstructions, and optimizing viewing angles swiftly via a single action, consequently enabling rapid, convenient, and efficient 3D imaging. Recent technologies, such as video US, have also emerged as a promising imaging procedure to evaluate suction patterns of the amniotic fluid during the gestational period (94). Relevant information about the fetal suctioning apparatus can be obtained and utilized for planning post-partum performance enhancement.
None of the identified studies reported the detection or appraisal of fetus positions or postures, during intrauterine life through AUS. The early detection of these habits is of the utmost importance because these vicious postures are likely to be maintained after birth and present as a risk factor for cranial asymmetries (95,96). In turn, plagiocephaly might be directly associated with developmental delays, practical difficulties in sports and everyday life, and significant deleterious impacts on children’s psychological functions (97). If promptly detected during GUS, a timely design can instead be developed through the collaboration of dental doctors, surgeons, neurologists, and rehabilitation therapists.
Apart from its associated clinical benefits, GUS images have also been shown to improve maternal relationships. Based on a randomized clinical trial carried out in a teaching hospital and clinic system-affiliated locations in Omaha (USA), maternal interaction with ultrasonographic materials (either regular 2D- or 3D-printed) led to more substantial enhancements in maternal-fetal attachment when compared to sole reliance on ultrasonography (98). Remarkably, the interaction effect between 3D-printed models suggested that the increase in the maternal antenatal attachment scale global score from the initial measurement was 3.75 points higher for the 3D-printed model group compared to the ultrasonography-only group (95% CI: 1.40 to 6.10, P value =0.002) (98). Similar outcomes were noted for the subscales concerning attachment quality and the duration spent contemplating the fetus. Considering these non-clinical outcomes, our research team believes that US images could alternatively be used for improving both professional observations and the parent/child relationship, particularly when an orofacial pathology is identified. The images themselves could prove useful in providing parents with a visualization of the neonates’ future facial characteristics and suggest potential interventions the neonate might need in the long run. Therefore, GUS offer not only a critical tool for ameliorated clinical practice, but also hold significant implications for parental relationships.
GUS serve as a cornerstone in fetal medicine, offering a primary and indispensable tool for the assessment of the developing fetus in utero (including orofacial features). Its predominant use (often by physicians) lies in its diagnostic capabilities, allowing healthcare professionals specialized in fetal medicine to closely monitor fetal growth and development. Nevertheless, the use of this imaging technique might (and should) be more utilized by dental doctors worldwide, suggesting an underutilization of these imaging exams to-date. Dental specialists have an intimate knowledge with cranial and facial development singularities and should be more familiarized with GUS images in routine clinical practice. Major reasons for the underuse of AUS within the field of dentistry to date might be associated with a lacking connection between sonographers and obstetricians, an insufficient number of screenshots targeting the craniofacial profile, or limited dental office visits during pregnancy. Therefore, we emphasize the importance of collaborative and patient-centered care delivery among different healthcare specialists, particularly physicians and dentists, to better detect and manage orofacial disorders.
The scoping review undertaken holds some limitations that warrant acknowledgment. Firstly, due to the nature of scoping reviews aiming for breadth rather than depth, there might be potential gaps in the comprehensiveness of the literature coverage. Despite employing systematic search strategies across multiple databases, the possibility of overlooking relevant studies cannot be entirely ruled out. Additionally, as scoping reviews involve a narrative synthesis of findings rather than a rigorous quality assessment, the quality and methodological rigor of included studies might vary significantly. This could impact the overall reliability and generalizability of the conclusions drawn from the reviewed literature. Additionally, we set a minimum number of patients to be enrolled in each individual study, which might have limited the amount of included studies. Despite the aforementioned limitations, our manuscript has extensively summarized the findings from various studies related to the detection and assessment of orofacial abnormalities using GUS techniques. It provides a comprehensive overview of the studies, their findings, and the effectiveness of US in identifying these abnormalities during different stages of pregnancy.
Conclusions
The findings emphasize how these AUS images can identify abnormalities, such as facial clefts, palate deformities, fetal micrognathia and glossoptosis. In addition, available evidence highlights the suitability of GUS in defining pregnancy termination based on major orofacial abnormalities. Ultimately, the need for continued advancements, standardized protocols, and interdisciplinary collaborations to enhance diagnostic accuracy is imperative to improve prenatal care for expectant parents worldwide.
Acknowledgments
The authors wish to thank Anneliese Arno (Evidence for Policy & Practice Centre, University College London, London, United Kingdom, and School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia) for granting complimentary access to Covidence® (Veritas Health Innovation, Melbourne, Australia).
Funding: None.
Footnote
Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://jphe.amegroups.com/article/view/10.21037/jphe-24-59/rc
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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jphe.amegroups.com/article/view/10.21037/jphe-24-59/coif). I.J.B.d.N. is an active Cochrane member and serves as an unpaid editorial board member of Journal of Public Health and Emergency from April 2024 to March 2026. The author affiliated with the World Health Organization (WHO) is alone responsible for the views expressed in this publication, which do not necessarily represent the decisions or policies of the WHO. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Cite this article as: Chedid SJ, De Fantini SM, Deeken G, Vasanthan LT, Leite HV, Caldas JVJ, Borges do Nascimento IJ. Antenatal ultrasound (AUS) and the detection of cranio- and orofacial malformations—a scoping review. J Public Health Emerg 2025;9:5.