Correspondence to Dr Sara Ornaghi; [email protected]
STRENGTHS AND LIMITATIONS OF THIS STUDY
Clearly described statistical methods with an a priori calculation of sample size planning to include a large cohort of uncomplicated low-risk singleton pregnancies with clearly defined inclusion and exclusion criteria, and with reporting of the results in the form of tables of fitted centile values.
A prospective cross-sectional design with consecutively enrolled patients undergoing ultrasound assessment and cavum septi pellucidi’s (CSP’s) measurements by multiple expert sonographers.
Accurate method of estimation of gestational age and of CSP’s measurement techniques, with ultrasound quality control measures, including image storage and review by expert maternal-fetal medicine physicians and intraobserver and interobserver variability assessment.
Single centre study conducted in an academic maternity centre located in Northern Italy.
No long-term neonatal follow-up for those infants with normal antenatal and postnatal assessment.
Introduction
The cavum septi pellucidi (CSP) is a fluid-filled cavity box situated on the midline between the medial walls of the two lateral ventricles, placed above the fornix and below the corpus callosum (CC).1 2 Although the CSP contains liquor, it does not have direct communication with the ventricular system of the fetal brain and the liquid accumulates by diffusion through the septum pellucidi.3 In a minority of cases, the CSP can extend caudally creating a pocket close to the distal part of the CC; this variant is commonly defined as ‘Cavum Vergae’.4
The formation of the CSP begins at 14 weeks and is completed around 17 weeks.5 6 Its development is directly related to that of the CC; thus, a normal CSP indirectly indicates a correct development of the CC and of the midline of the fetal brain. For this reason, the CSP is a crucial landmark for the ultrasonographic study of the fetal central nervous system (CNS),7 and its visualisation in all the three axial views (transventricular, transthalamic and transcerebellar) is mandatory during routine obstetric scans between 17 and 37 weeks’ gestation.8–10 Lack of visualisation of the CSP during this time frame can associate with midline malformations, such as partial or complete agenesis of the CC and alobar or semilobar holoprosencephaly, or syndromes, including Apert syndrome, Chiari type II syndrome and septo-optic dysplasia.5 6 11–14 However, it is less clear whether an altered biometry or shape of the CSP consistently associates with fetal CNS malformations or syndromes. Increased width of the CSP has been reported in cases with chromosomal abnormalities, including trisomy 13, 18 and 21, and microdeletion 22q11, and with neurodevelopmental delay.1 12 15–18 Of note, the available ultrasound guidelines do not report specific recommendations on the assessment of CSP’s size and shape,8–10 thus leaving to the expertise of the sonographer and, thus, to a subjective evaluation, the identification of potential CSP’s anomalies.
To address this gap, some authors have attempted to create reference charts of the fetal CSP width.1 4 12 13 15 19–26 Yet, methodological limitations can be identified in these studies, including being based on retrospectively collected data,1 12 13 the use of non-standardised CSP measurements4 19 or inaccurate dating method,4 19 23 the inclusion of high-risk pregnancies,1 19 21 the lack of quality control4 15 19 23 or of postnatal follow-up,4 12 15 19–21 23 24 and a relatively small sample size,1 4 12 13 20 23–26 thus limiting the clinical validity of such reference charts and forcing the sonologist to choose one of the published references or to use multiple nomograms. In addition, only one study attempted to build reference charts not only for the CSP’s width but also its length and length-to-width ratio,13 with the latter being suggested to help in the identification of CC’s partial agenesis if abnormal.13 27 28
In the last decade, there has been a drive for improvement in reporting results in ultrasound-derived reference ranges and reporting results of obstetrical and gynaecological studies more generally.29 30 It is in this context that we have designed our study, which aims to create methodologically robust reference charts for the width, length and length-to-width ratio of the CSP through a prospective data collection from a cohort of male and female fetuses in a low-risk singleton pregnant population. This prospective approach enables the ad hoc selection of the information to be collected and the use of standardised measurements, improving the uniformity of variable coding and reducing the imprecision of measures and the risk of missing data, as well as mitigating the risk of selection bias.
Methods and analysis
Aims of the study
The primary aim of our study is to draw reference charts of the CSP’s width, length and length-to-width ratio as a function of gestational age (GA) and Biparietal Diameter (BPD).
The study also comprises five secondary objectives: (1) to evaluate fetuses excluded from the construction of reference charts due to chromosomal and/or anatomical abnormalities identified during gestation or postnatal follow-up using the reference charts we have constructed; (2) to validate our reference charts with pregnancies managed at our institution to verify their applicability in clinical practice and diagnostic performance; (3) to estimate the frequency of intracranial and extracranial abnormalities associated with a regular CSP; (4) to standardise the need for a second level ultrasound assessment for the study of the fetal CNS; and (5) to assess the prevalence of postnatal clinical neuropsychological correlates in children with prenatal findings of a non-regular CSP.
Study setting and design
The study will be conducted at the Unit of Obstetrics, Foundation IRCSS San Gerardo dei Tintori, Monza, Italy. The research centre is an academic maternity unit with approximately 2600 births per year.
The study will be monocentric and cross-sectional with a prospective data collection, including consecutive pregnant women accessing our unit for an antenatal ultrasound evaluation.
Recruitment and sample
Participants will be consecutively enrolled at a single academic maternity centre located in Northern Italy (Foundation IRCCS San Gerardo dei Tintori). Active engagement of women will be pursued through public dedicated website communications (Foundation IRCCS San Gerardo dei Tintori’s Facebook page), digital content and leaflets reporting on the characteristics of the study.
All pregnant women accessing our obstetrical unit for an ultrasound scan will be assessed for inclusion and exclusion criteria available at the time of sonographic assessment. Precisely, the inclusion criteria are as follows: (1) singleton pregnancy; (2) maternal age between 18 and 45 years; (3) GA between 190/7 and 366/7 weeks’ gestation; and (4) certain pregnancy dating by first trimester ultrasound with crown-rump length measurement. Women will be excluded if any of the following is present: (1) unreliable measurement of the CSP; (2) pregestational chronic conditions (eg, chronic hypertension, diabetes mellitus type I and II, renal disease; (3) gestational diabetes requiring pharmacological therapy (metformin or insulin); (4) hypertensive disorders of pregnancy31; (5) fetal growth restriction as diagnosed according to the Delphi criteria32; (6) fetal anomalies or congenital malformations and chromosomal or genetic abnormalities diagnosed during pregnancy or postnatally; (7) stillbirth; (8) preterm birth <370/7 weeks’ gestation; and (9) inclusion criteria not respected.
If inclusion and exclusion criteria available at the time of sonographic assessment are fulfilled, women and their partners will be provided with detailed information regarding the study. In case of acceptance to participate in the study, women will be asked to sign a written informed consent. After this, the ultrasound scan will be performed.
As per international guidelines,8 the axial section of the fetal head in the transventricular plane will be obtained and the CSP visualised. The CSP’s width and length will be measured and recorded. CSP measurements will be taken using the inner-to-inner technique.4 Precisely, for the CSP width, the callipers will be positioned at the level of the inner hyperechogenic margin at its midpoint, as described by Abele et al and Karl et al,1 13 and not at its largest point,4 19 since some fetuses may have a triangular-shaped CSP14 (figure 1). For assessing the CSP length, the callipers will be positioned at the level of the hyperechogenic margins anteriorly, the callosal sulcus and posteriorly, the fornix (figure 1). Each measurement will be performed three times, and the mean value determined and recorded. All measurements will be carried out by experienced, trained sonographers using a Samsung Philips Affinity 70 e Philips IU 22 (probe convex 5–2).
Figure 1. Measurement of the cavum septi pellucidi’s width and length with the inner-to-inner technique (transventricular plane).
All images will be stored for subsequent quality review by two experienced maternal-fetal medicine physicians. In case of disagreement on the quality of the image, the review will be performed by a third expert; if concordance is still not achieved, then the case will not be considered for charts’ construction. In addition, intraobserver and interobserver variability of CSP measurements will be assessed. For intraobserver variability, the two experienced maternal-fetal medicine physicians involved in image quality review will separately evaluate the same ultrasound image after at least 7 days of her/his initial measurement. For the interobserver variability, the two physicians will assess the same ultrasound image unaware of each other’s measurements.
If CSP cannot be clearly visualised or an abnormality of its morphology or size is suspected, the woman will be referred for a second level ultrasound assessment with a detailed investigation of the fetal CNS using a combined transabdominal and transvaginal approach (in case of a cephalic fetus), and a fetal brain MRI.8
Due to the study’s design, blinding of the sonographers acquiring the ultrasound image to the results of CSP measurements will not be possible.
All fetuses included in the study will undergo postnatal follow-up. Fetuses with a regular CSP according to the antenatal ultrasound assessment will receive a thorough clinical examination by a neonatologist at the time of hospital discharge. In turn, fetuses with an absent or abnormal CSP will receive a thorough clinical and neuropsychiatric examination and a brain ultrasound and MRI, as per our institutional protocol.
Inclusion and exclusion criteria will be additionally assessed after pregnancy completion and neonatal evaluation. Cases fulfilling inclusion and exclusion criteria, as previously listed, with a regular neonatal assessment, and in which the quality of the ultrasound images is deemed adequate during the review process, will be included in the construction of the reference charts.
The recruitment process is estimated to last 24 months (start date 1 June 2024—estimated end date 31 May 2026).
Data collection process and sample size
We will collect data regarding demographic characteristics, GA at ultrasound assessment, fetal gender and head biometry (BPD and circumference), presence or absence of CSP, size (width and length) and morphology of CSP, pregnancy course and delivery (GA and mode), Apgar score at 1 and 5 min, values of umbilical artery gas analysis at birth (pH, base excess, lactate), neonatal gender and birth weight and postnatal follow-up evaluation. All data will be electronically organised in an anonymous form and securely stored on laptops that will be password protected. At completion of the study, all data will be disposed of properly (Data Protection Code, 2003; General Data Protection Regulation - GDPR, 2018).
A paper logbook containing information on all women screened for eligibility and the reasons for ineligibility or lack of inclusion if eligibility is met will be kept separately, in a locked cabinet accessible only by the principal investigator and the research assistants. This logbook will also contain research codes and personal data of enrolled women.
A data monitoring committee was not deemed necessary for the current study due to the following reasons: (1) we do not anticipate any disadvantage or risk in taking part in this research; (2) participation in the study is voluntary and women will be free to withdraw from the study at any time, continuing their obstetrical care as per institutional protocols.
In order to achieve appropriate statistical power required for constructing reliable reference charts, a minimum sample size of 80 fetuses for each GA group of interest will be considered.33–37 A minimum of 80 fetuses per GA group yields 90% CIs of approximately 6.3rd–15.1st for the 10th centile and 1.4th–6.8th for the 3rd centile. Similarly, intervals for the 90th and 97th centiles are 84.9th–93.7th and 94.2nd–98.6th, respectively. These estimates are conservative, as they are based on pointwise calculations that do not account for the dependency between distribution across GA. In practice, the use of smoothing models reduces uncertainty and improves the precision of centile estimation.38
We will divide our population into six groups according to the GA when the ultrasound scan will be performed, with each group covering a 3-week interval starting at 190/7 until 366/7 weeks. Precisely, group 1 will include cases from 190/7 to 216/7 weeks, group 2 from 220/7 to 246/7 weeks, group 3 from 250/7 to 276/7 weeks, group 4 from 280/7 to 306/7 weeks, group 5 from 310/7 to 336/7 weeks and group 6 from 340/7 to 366/7 weeks.
For intraobserver and interobserver variability, the intraclass correlation coefficient will be evaluated using a two-way mixed model with absolute agreement.
Statistical analysis
A descriptive analysis of the population will be performed, reporting maternal and fetal characteristics as absolute frequencies (percentages) for qualitative variables, and as mean±SD or median (IQR) for quantitative variables, depending on their distribution. The construction of the charts will be performed for GA between 190/7 and 366/7 weeks’ gestation using a cross-sectional sample, that is, each pregnancy will contribute a single measurement.
Before tracing the charts, data will be checked for consistency to identify outliers in two sequential steps. First, values falling outside very broad predefined thresholds, representing biologically implausible measures, will be identified. Where possible, outliers so identified will be corrected by referring to the original records (eg, to resolve computation or transcription errors); otherwise, they will be excluded from the analysis. Next, we will identify values lying beyond the group of GA-specific mean±4×SD, computed from the study population (internal consistency check). Outliers identified by this second step will be reviewed individually: if a transcription error is found, they will be corrected; if the values are deemed biologically plausible, they will be retained; otherwise, they will be excluded.
The fetal charts will be traced using the CG-LMS method,39 which is regarded as the gold standard for tracing anthropometric charts. In addition, the use of alternative modelling approaches, such as parametric models derived from the EMGF (Extended Mechanistic Growth Function) method,40 will be explored.
The need to create sex-specific charts will be evaluated if a relevant difference between male and female fetuses is observed.20 41
CSP charts will be plotted against GA and BPD; also, the possibility to chart the CSP/BPD ratio against GA will be assessed.
The charts will be presented in the form of both graphs and tables with numerical values of the main centiles in function of GA. They will also be parameterised in terms of smooth GA-specific curves L, M and S, just as in the Cole and Green LMS (CG-LMS) model39; goodness of fit testing will demonstrate whether the curves obtained describe accurately the structure of the raw data.42
Patient and public involvement
There is no patients’ involvement in the study design or conduct. Participating women and their partners will be fully informed about the findings of the study through dedicated online communications (Foundation IRCCS San Gerardo dei Tintori’s Facebook page) and in-person events.
Ethics and dissemination
Ethical considerations
Ethical approval for this study was obtained by the Lombardy Ethics Committee n.3 (15 December 2023, n. 4239) prior to the commencement of the research. Participants involved in this study will be fully informed about the aim of the research and will be asked to sign an individual written consent form. Women will be free to decline participation or to withdraw at any time. All participants will be provided with the name, telephone number and email of the principal investigator, in case any question about the study should arise.
All the procedures will be consistent with the Declaration of Helsinki ethical principles for research involving human subjects.43 The procedures do not imply any change to mother–infant care programmes in place at our institution.
Dissemination plan
The dissemination plan includes the presentation of the findings at national and international scientific meetings, and the publication in peer-reviewed scientific journals in the field of obstetrics and fetal medicine.
The target audience for this study includes different stakeholders: clinicians, particularly obstetricians and midwives, policymakers, healthcare managers, researchers, and the public, especially women in their reproductive age. The availability of reference charts for the fetal CSP width and length in relation to GA and BPD constructed with an appropriate methodology is of utmost importance as it will improve the antenatal diagnosis of truly pathologic phenotypes through standardization of fetal CSP assessment.
Ethics statements
Patient consent for publication
Consent obtained directly from patient(s).
X @sara_ornaghi
Contributors RR: data curation, investigation, writing—original draft, writing—review and editing. MV: conceptualisation, investigation, writing—review and editing. ESp: data curation, formal analysis, methodology. PC: data curation, investigation. LL: data curation, investigation. ESa: data curation, investigation. SC: investigation, writing—review and editing. PV: conceptualisation, writing—review and editing. AL: writing—review and editing. SO: conceptualisation, data curation, investigation, supervision, writing—original draft, writing—review and editing. SO is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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Abstract
Introduction
The cavum septi pellucidi (CSP) is a fluid-filled cavity box situated on the midline between the medial walls of the two lateral ventricles and placed above the fornix and below the corpus callosum. The formation of the CSP begins at 14 weeks and is completed around 17 weeks.
A regular CSP indirectly indicates the correct development of the corpus callosum and the midline of the fetal brain. Therefore, its evaluation is mandatory during routine obstetric scans. The available guidelines do not report specific recommendations on the morphology or biometry of the fetal CSP, thus leaving to the experience of the operator and, thus, to a subjective evaluation, the identification of potential anomalies.
Our aim is to construct methodologically robust reference charts for the CSP’s width, length and length-to-width ratio in relation to gestational age and fetal biparietal diameter.
Methods and analysis
The REC-FAST study (Reference Charts for the Fetal cAvum SepTi pellucidi) is a prospective monocentric cross-sectional study on consecutively enrolled pregnant women accessing our Obstetric Unit at the Foundation IRCCS San Gerardo dei Tintori, Monza, Italy, for fetal ultrasound evaluation.
Women will be eligible if carrying an uncomplicated singleton pregnancy between 190/7 and 366/7 weeks’ gestation with a certain pregnancy dating by first trimester ultrasound with crown-rump length measurement, and if aged between 18 and 45 years.
After signing the informed consent, the ultrasound scan will be performed and the CSP’s width and length will be measured by means of the inner-to-inner technique and its morphology recorded.
In order to achieve the statistical power required for properly constructing reference charts, we will divide our population into six groups according to the gestational age when the ultrasound scan will be performed (each group will cover a 3-week interval starting at 190/7 until 366/7 weeks). A minimum sample size of 80 will be reached for each gestational age group. Before charting, the data will be checked for consistency to identify any outliers. Where possible, outliers will be corrected by comparing with the original values (computation errors); otherwise, such data will be excluded. The fetal charts will be traced using the Cole and Green-Lambda, Median, and Sigmamethod (CG-LMS); in addition, the use of alternative modelling approaches, such as parametric models derived from the Extended Mechanistic Growth Function method, will be explored.
Ethics and dissemination
Ethical approval for this study was obtained by the Lombardy Ethics Committee n.3 (15 December 2023) prior to the commencement of the research. Written informed consent will be obtained from all participants. Women will be free to decline participation or to withdraw at any time.
Findings will be presented at scientific meetings and published in peer-reviewed scientific journals in the field of obstetrics and fetal medicine. Also, they will be disseminated to study participants through dedicated online and in-person meetings and to the public through reach-out activities involving families and healthcare specialists.
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1 Unit of Obstetrics, Foundation IRCCS San Gerardo dei Tintori, Monza, Italy
2 Laboratorio Carlo Corchia - LCC, Florence, Italy
3 Unit of Obstetrics, Foundation IRCCS San Gerardo dei Tintori, Monza, Italy; School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
4 School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy