biparietal diameter at 11 to 13 weeks' gestation in fetuses with holoprosencephaly

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ORIGINAL ARTICLE Biparietal diameter at 11 to 13 weeksgestation in fetuses with holoprosencephaly Asma Khalil*, Aris Papageorghiou, Amar Bhide, Ranjit Akolekar and Basky Thilaganathan Fetal Medicine Unit, Academic Department of Obstetrics and Gynaecology, St Georges Hospital Medical School, London, UK *Correspondence to: Asma Khalil. E-mail: [email protected] ABSTRACT Objective Studies have suggested that fetuses with holoprosencephaly have smaller head size, demonstrated as early as the rst trimester. However, the majority of these cases were diagnosed in the second or third trimesters. The aim of this study was to investigate biparietal diameter (BPD) measured at 11 to 13 weeksgestation in fetuses with holoprosencephaly. Methods This was a retrospective study in which BPD was measured at 11 to 13 weeks in 34 fetuses with prenatal diagnosis of holoprosencephaly and 7775 unaffected controls. BPD values were converted into multiples of the expected median (MoM) after adjustment for crownrump length and maternal characteristics. Results The median gestational age at the BPD recording was 12.6 (interquartile range 12.313.0) weeks. The nuchal translucency was increased (3mm) in 58.8% of the cases. Aneuploidy was conrmed in 73.5% of the cases; the commonest was trisomy 13 (50.0%). BPD values at 11 to 13 weeks were below the 5 th centile in 32.4% of cases and below the 50 th centile in 67.6%. BPD MoM values were signicantly smaller than in the control group (median: 0.98; interquartile range: 0.901.06 vs 1.00; 0.961.04 MoM, p = 0.03). Conclusion Fetuses with holoprosencephaly have a smaller BPD in the rst trimester. This property may be useful in early diagnosis. © 2013 John Wiley & Sons, Ltd. Funding sources: None Conicts of interest: None declared INTRODUCTION Holoprosencephaly is a brain malformation resulting from incomplete midline cleavage of the prosencephalon between the 18th and the 28th day. The most widely used classication includes three major types according to the severity of the malformation: the alobar, semilobar, and lobar types. 15 Severe forms of holoprosencephaly are usually fatal, and those who survive suffer from major developmental disability. 6,7 Routine ultrasound at 11 to 13 weeksgestation offers an opportunity for screening for aneuploidy and early detection of structural abnormalities. 810 The rst trimester diagnosis of alobar holoprosencephaly has been based on the visualization of a single ventricle. 11,12 Sepulveda and colleagues have suggested that failure to identify the butterysign of the choroid plexus at 11 to 13 weeks is a warning sign of holoprosencephaly. 13 However in a large study that also reviewed all the studies that investigated the detection of structural abnormalities at 11 to 13 weeks, the detection rate of holoprosencephaly was 78% in the rst trimester. 8 First trimester diagnosis would potentially allow parents more time to receive counseling and to consider their options, including early safer termination of the pregnancy. Holoprosencephaly is a rare anomaly, and therefore, the available literature on the prenatal diagnosis of holopro- sencephaly is rather limited to mainly case series and few population or registry studies. 12,1421 Few authors have reported a smaller than expected head size in fetuses with holopro- sencephaly. 12,15 In the study by Blaas et al. that included 30 fetuses with a prenatal diagnosis of holoprosencephaly, 17 cases (57%) had biparietal diameter (BPD) values, which were 5 to 37 mm less than the corresponding mean. 12 The mean gestational age (GA) in this study was 21 weeks, ranging between 9 and 37 weeksgestation, and only two fetuses were diagnosed before 13 weeksgestation. 12 In a more recent study of 51 fetuses with a prenatal ultrasound diagnosis of holoprosencephaly between 1990 and 2005, the diameter of the head was below the 5 th centile in 60% of the fetuses in the rst trimester and 92% in the third trimester. 15 The mean GA at diagnosis in this study was 32.3 weeks in 1990, 18.8 weeks in 2005, and 21.9 weeks throughout the 15-year time span of this study. 15 Only seven fetuses in this study were diagnosed with holoprosencephaly at 11 to 13 weeksgestation. A recent study by Sepulveda and Wong, including more than 11 000 screened fetuses at 11 to 13 weeks, Prenatal Diagnosis 2014, 34, 134138 © 2013 John Wiley & Sons, Ltd. DOI: 10.1002/pd.4269

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Page 1: Biparietal diameter at 11 to 13 weeks' gestation in fetuses with holoprosencephaly

ORIGINAL ARTICLE

Biparietal diameter at 11 to 13weeks’ gestation in fetuses withholoprosencephalyAsma Khalil*, Aris Papageorghiou, Amar Bhide, Ranjit Akolekar and Basky Thilaganathan

Fetal Medicine Unit, Academic Department of Obstetrics and Gynaecology, St George’s Hospital Medical School, London, UK*Correspondence to: Asma Khalil. E-mail: [email protected]

ABSTRACTObjective Studies have suggested that fetuses with holoprosencephaly have smaller head size, demonstrated as earlyas the first trimester. However, the majority of these cases were diagnosed in the second or third trimesters. The aim ofthis study was to investigate biparietal diameter (BPD) measured at 11 to 13 weeks’ gestation in fetuses withholoprosencephaly.

Methods This was a retrospective study in which BPD was measured at 11 to 13weeks in 34 fetuses with prenataldiagnosis of holoprosencephaly and 7775 unaffected controls. BPD values were converted into multiples of the expectedmedian (MoM) after adjustment for crown–rump length and maternal characteristics.

Results The median gestational age at the BPD recording was 12.6 (interquartile range 12.3–13.0) weeks. The nuchaltranslucency was increased (≥3mm) in 58.8% of the cases. Aneuploidy was confirmed in 73.5% of the cases; thecommonest was trisomy 13 (50.0%). BPD values at 11 to 13weeks were below the 5th centile in 32.4% of cases and belowthe 50th centile in 67.6%. BPDMoMvalueswere significantly smaller than in the control group (median: 0.98; interquartilerange: 0.90–1.06 vs 1.00; 0.96–1.04 MoM, p=0.03).

Conclusion Fetuses with holoprosencephaly have a smaller BPD in the first trimester. This property may be useful inearly diagnosis. © 2013 John Wiley & Sons, Ltd.

Funding sources: NoneConflicts of interest: None declared

INTRODUCTIONHoloprosencephaly is a brain malformation resulting fromincomplete midline cleavage of the prosencephalon betweenthe 18th and the 28th day. The most widely used classificationincludes three major types according to the severity of themalformation: the alobar, semilobar, and lobar types.1–5 Severeforms of holoprosencephaly are usually fatal, and those whosurvive suffer from major developmental disability.6,7 Routineultrasound at 11 to 13weeks’ gestation offers an opportunityfor screening for aneuploidy and early detection of structuralabnormalities.8–10 The first trimester diagnosis of alobarholoprosencephaly has been based on the visualization of asingle ventricle.11,12 Sepulveda and colleagues have suggestedthat failure to identify the ‘butterfly’ sign of the choroid plexusat 11 to 13weeks is a warning sign of holoprosencephaly.13

However in a large study that also reviewed all the studies thatinvestigated the detection of structural abnormalities at 11 to13weeks, the detection rate of holoprosencephaly was 78% inthe first trimester.8 First trimester diagnosis would potentiallyallow parents more time to receive counseling and to considertheir options, including early safer termination of the pregnancy.

Holoprosencephaly is a rare anomaly, and therefore, theavailable literature on the prenatal diagnosis of holopro-sencephaly is rather limited to mainly case series and fewpopulation or registry studies.12,14–21 Few authors have reporteda smaller than expected head size in fetuses with holopro-sencephaly.12,15 In the study by Blaas et al. that included 30fetuses with a prenatal diagnosis of holoprosencephaly, 17 cases(57%) had biparietal diameter (BPD) values, which were 5 to37mm less than the corresponding mean.12 The meangestational age (GA) in this study was 21weeks, ranging between9 and 37weeks’ gestation, and only two fetuses were diagnosedbefore 13weeks’ gestation.12 In a more recent study of 51 fetuseswith a prenatal ultrasound diagnosis of holoprosencephalybetween 1990 and 2005, the diameter of the head was belowthe 5th centile in 60% of the fetuses in the first trimester and92% in the third trimester.15 The mean GA at diagnosis in thisstudy was 32.3weeks in 1990, 18.8weeks in 2005, and 21.9weeksthroughout the 15-year time span of this study.15 Only sevenfetuses in this study were diagnosed with holoprosencephaly at11 to 13weeks’ gestation. A recent study by Sepulveda andWong,including more than 11000 screened fetuses at 11 to 13weeks,

Prenatal Diagnosis 2014, 34, 134–138 © 2013 John Wiley & Sons, Ltd.

DOI: 10.1002/pd.4269

Page 2: Biparietal diameter at 11 to 13 weeks' gestation in fetuses with holoprosencephaly

has reported that the BPDwas below the 5th centile in 40% of thefetuses with holoprosencephaly.22

Recent studies have reported that BPD at 11 to 13weeks’gestation is a potentially useful marker for identifying fetuseswith open spina bifida,23–25 whereas a recent study has reportedthat fetuses with triploidy had larger BPD than expected byGA.26 The aim of our study was to investigate the BPDmeasuredat 11 to 13weeks’ gestation in fetuses with holoprosencephaly.

METHODSThis was a retrospective study of fetuses in whichholoprosencephaly was detected at 11 to 13weeks’ gestation.Cases were identified by searching the ViewPoint database(ViewPoint 5.6.8.428, ViewPoint Bildverarbeitung GmbH,Weßling, Germany) in the Fetal Medicine Unit, St George’sHospital, for scans performed between March 1997 and April2012. A control group was randomly selected from the samedatabase for comparison. The control group consisted of low-risk, uncomplicated singleton pregnancies resulting in the livebirth of a phenotypically normal neonate (n= 7775). In thecontrol group, any pregnancies resulting in fetal demise orwhere the fetus had a structural abnormality, aneuploidy, orgenetic syndrome were excluded. Data ascertained includedmaternal characteristics, GA, crown-rump length (CRL), BPD,nuchal translucency (NT) measurement, and any structuralmalformations at the first trimester scan; invasive procedures;karyotype; second trimester ultrasound examination findings;fetal or neonatal outcome; and postmortem examinationfindings, if performed. GA was calculated from the CRLmeasurement using the equation of Robinson and Fleming.27

The BPD was measured on a transverse view of the fetal headin a plane showing both thalami and the third ventricle, andthe calipers were placed on the outer borders of the skull(out–out).28,29 Maternal characteristics recorded were age,parity, racial origin, smoking status during pregnancy, pre-

pregnancy diabetes, and method of conception. The maternalweight and height were measured at the time of screening,and the body mass index was calculated. Data on pregnancyoutcomes were collected from the hospital maternity recordsor the general medical practitioners of the women.

Statistical analysisCategorical data were presented as number (%) and werecompared using the Fisher’s exact test or chi-squared test.Continuous data were presented as median [interquartile range(IQR)]. The D’Agostino and Pearson omnibus test was used toassess the normality of the data. Multiple regression analysiswas used in the control group to determine if any maternal orpregnancy characteristics, including maternal age, body massindex, parity, ethnic origin, smoking status, diabetes, CRL, andmethod of conception were significant predictors of BPD.24

These algorithms were then used to convert the measured BPDin all cases and controls into multiples of the expected median(MoM) in the unaffected group. Nonparametric analysis usingMann–Whitney U-test was then used to compare the medianBPD MoMs between the two groups. The measured BPD valueswere compared with the reference ranges published byKurmanavicius et al.30 and Salomon et al.31 The analysis wasperformed using the statistical software packages SPSS 18.0 (SPSSInc., Chicago, IL, USA), STATA 11 (release 11.2. College Station,TX, USA), and GRAPHPAD PRISM

® 5.0 for Windows (InStata,GraphPad Software Inc., San Diego, CA, USA).

RESULTSThe study cohort consisted of 34 fetuses with prenatal diagnosisof holoprosencephaly and 7775 normal pregnancies with BPDmeasurement performed at 11 to 13weeks. There were 33singleton pregnancies and one dichorionic diamniotic twinpregnancy. The maternal and pregnancy characteristics of thesetwo groups are shown in Table 1. The BPD measurement was

Table 1 Maternal and pregnancy characteristics in the outcome groups

Maternal characteristics Controls (n=7775) Holoprosencephaly (n=34) P-value

Maternal age (years), median (IQR) 32.0 (28.0–35.0) 31.0 (28.0–36.3) 0.610

Body mass index (kg/m2), median (IQR) 24.1 (21.6–27.7) 23.5 (21.2–27.1) 0.326

Crown rump length (mm), median (IQR) 62.3 (57.0–68.7) 59.9 (55.0–63.2) 0.022

Nuchal translucency (mm), median (IQR) 1.6 (1.5–1.9) 3.1 (2.2–5.7) <0.001

Gestational age (weeks), median (IQR) 12.6 (12.1–13.0) 12.6 (12.3–13.0) 0.827

Ethnicity, n (%)

Caucasian 5138 (66.1) 24 (70.6) 0.710

African 1151 (14.8) 4 (11.8) 0.798

Asian 1479 (19.1) 6 (17.6) 1.00

Nulliparous, n (%) 3259 (41.9) 15 (44.1) 0.932

Cigarette smoker, n (%) 428 (5.5) 0 (0) 0.303

Pre-pregnancy Diabetes, n (%) 196 (2.5) 0 (0) 0.698

Spontaneous Conception, n (%) 7536 (96.9) 33 (97.1) 0.650

Biparietal diameter (mm), median (IQR) 21.2 (19.6–23.0) 20.0 (18.2–21.1) 0.002

IQR, interquartile range.Comparison between the groups was performed using Mann–Whitney U-test for continuous variables and X2 test and Fisher’s exact test.

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performed at a median GA of 12.6 (IQR 12.3–13.0) weeks. TheNT was increased (3mm or more) in 58.8% of the cases. All thecases included in this study had alobar holoprosencephaly,except one case where the diagnosis was semilobar holopro-sencephaly. Aneuploidy was confirmed in 73.5% of the cases;of those, 64.0% had associated major structural abnormalities.The associated abnormalities included exomphalos, megacystis,and facial and cardiac defects. The commonest chromosomalabnormality was trisomy 13 (50.0% of the cases and72% of the detected chromosomal abnormalities). Other chromo-somal abnormalities were trisomy 18, triploidy, trisomy 10, andunbalanced translocation between chromosome 6 and chro-mosome 13. The majority of the cases underwent termination ofthe pregnancy (91.2%) following the diagnosis, except three caseswhere the pregnancy ended in miscarriage prior to 15weeks andpostmortem examination was not undertaken.

Fetuses with holoprosencephaly had significantly smaller BPDand CRL at 11 to 13weeks compared with the control group(p=0.002 and p=0.022, respectively), whereas the NT wassignificantly larger (p< 0.001) (Table 1). There were no significantdifferences between the two groups in thematernal characteristicsor GA at the first trimester scan. When fetuses with trisomy18 (n=4) were excluded from the analysis, the CRL in the caseswas similar to that in the control group (p=0.103), whereas theBPD remained significantly smaller (p< 0.003).

Individual BPD values at 11 to 13weeks were plotted inrelation to the CRL on the reference chart developed by Salomonet al.31 (Figure 1). Of the 34 fetuses with holoprosencephaly, 11(32.4%) had BPD values below the 5th centile, and 23 (67.6%)had BPD values below the 50th centile at the first trimester scan.The extent of reduction was not related to the CRL (p=0.512).TheBPDmeasurements were also plotted on the reference rangefor BPD by Kurmanavicius et al.30 (Figure 2). The BPD values at11 to 13weeks were below the 5th centile in 11/34 (32.4%) fetusesand below the 50th centile in 29/34 (85.3%).

In fetuses with holoprosencephaly, the BPD MoM value wassignificantly smaller than in the control group (median: 0.98;IQR: 0.90–1.06 vs 1.00; 0.96–1.04 MoM, p = 0.03). The MoMvalues in fetuses with holoprosencephaly were plotted on thenormal range for unaffected pregnancies (Figure 3).

DISCUSSIONThe findings of this study confirm that BPD measurements at 11to 13 weeks’ gestation are reduced in fetuses withholoprosencephaly. Almost a third (32%) of the fetuses withholoprosencephaly in our study had a BPD <5th centile at thisearly gestation. Our findings are in agreement with those recentlyreported by Sepulveda andWong, where 40% of the fetuses had aBPD <5th centile at 11 to 13 weeks’ gestation.22 In their study,Sepulveda and Wong have demonstrated that the butterfly signappears to be a highly sensitive marker in the first trimester asall the fetuses with holoprosencephaly had absent butterflyappearance of the choroid plexus, whereas the BPDmeasurements had a lower sensitivity with only 40% had a BPD

Figure 1 Biparietal diameter measurements in 35 fetuses withholoprosencephaly, measured at 11 to 13-week scan, plotted againstthe crown–rump length on the biparietal diameter reference range ofSalomon et al.31. The solid line represents the 50th centile, and thebroken line represents the 5th centile. The figure shows 11/34 (32.4%)fetuses below the 5th centile and 23/34 (67.6%) below the 50th centile

Figure 2 Biparietal diameter in 47 fetuses with prenatal diagnosis ofholoprosencephaly plotted on a modified biparietal diameterreference range of Kurmanavicius et al.30. The solid line representsthe 50th centile, and the broken lines represent the 5th and 95th

centiles. The figure shows 11/34 (32.4%) fetuses below the 5th centileand 29/34 (85.3%) below the 50th centile

Figure 3 Distributions of biparietal diameter multiples of the expectedmedian values in fetuses with holoprosencephaly plotted on the normalrange (50th, 10th, and 5th centiles) for unaffected pregnancies

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<5th centile.22 Fetal BPD values in the first trimester couldpotentially be a useful alert to the presence of brain or neural tubedefects, for example, spina bifida.23–25 Our findings accord withthose reported by other groups.12,15 Our data also demonstratethat the proportion of cases with BPD <50th centile differsaccording to the reference curves used. When Salomon’s chartwas used, 23/34 (67.6%) fetuses with holoprosencephaly hadBPD values below the 50th centile.31 However, the correspondingproportionwas 29/34 (85.3%) fetuses when Kurmanavicius’s chartwas used.30 The proportion of cases with BPD<5th centile was thesame (32.4%). This highlights the fact that first-trimester growthcharts and predictive equations based on CRL instead of GA arelikely to bemore accurate.31 A proportion of our cases had trisomy18, which demonstrate early-onset growth restriction and asmaller CRL measurement.32

The smaller BPD in fetuses with holoprosencephalycould potentially be explained by a smaller brain volume.Bartholomeusz et al., using brain magnetic resonance imaging,have demonstrated that the head circumference is an accurateindication of brain volume.33 More recently, Whitehouse et al.have shown that children with language impairment are morelikely to have a small head size at birth.34 The authors havespeculated that smaller head size at birthmay even relate tomoreglobal cognitive difficulties.34 Similar to open spina bifida, thereduced head circumference in fetuses with holoprosencephalyseems to be a progressive phenomenon. Recent studies havereported smaller BPD measurements in fetuses with spina bifidain approximately 50% of the cases at 11 to 13weeks and in up to70% of the cases at 16 to 24weeks.23–25,35,36 In the study byWenghoefer et al., the prevalence of small head size in fetuses withholoprosencephaly increased from 60% in the first trimester to71% and 92% in the second and third trimesters, respectively.15

The prevalence of chromosomal abnormalities in our study was74%, which is similar to that reported in other studies.14,15 Thecorresponding figure was 78% in the Dutch study involving 51cases of holoprosencephaly and 66% in the large screening studyat 11 to 13weeks involving 57119 pregnancies.14,15 However, thisrate of aneuploidy is higher than that reported by other authors,varying between 36% and 46%.12,16,17,19,37 This might be explainedby the potential poor ascertainment in older studies. Thecommonest chromosomal abnormality in our study was trisomy13 (50%). This is also consistent with other studies, where theprevalence of trisomy 13 in fetuses with holoprosencephaly hasbeen reported to be 59% in the study by Wenghoefer et al.15 and57% in the screening study by Kagan et al.14,15 Similarly, previousstudies have reported the presence of holoprosencephaly, varyingfrom 27% to 70%, in trisomy 13 cases.38,39 Other chromosomalabnormalities in our cohort included trisomy 18, triploidy, andtrisomy 10, which have also been reported in previous studies in

association with holoprosencephaly.12,14–16,37,40–42 As BPD belowthe 5th percentile has been described in fetuses with open spinabifida and holoprosencephaly, we recommend that these casesshould be referred to a fetal medicine specialist for a detailedultrasound examination to exclude associated abnormalities, inparticular the spine and the brain. This ultrasound examinationshould ideally take place in the first trimester, and the operatormight consider performing transvaginal ultrasound examinationif optimal views could not be achieved using transabdominalultrasound. The operator might also consider performing afollow-up ultrasound at 16 to 22weeks.

The high rate of termination of the pregnancy (TOP) in ourcohort is similar to what other studies have reported.14 In thislarge screening study including 57 119 cases, there were 44cases of holoprosencephaly diagnosed at 11 to 13weeks’gestation, and all underwent TOP at the request of theparents.14 The prevalence of holoprosencephaly varies from1 : 240 before 10weeks43 to 1 : 1298 at 11 to 13weeks,14 1 : 8000in the second trimester,17 and 0.5–1 per 10 000 at birth.12,16

This discrepancy in the prevalence of holoprosencephaly islargely explained by high rate of intrauterine death of theassociated chromosomal abnormalities, high rate of TOP, poorascertainment, and under reporting in registries of congenitalanomalies.44

The limitations of our study include its retrospective design andthe lack of head circumference measurements. The strengths ofour study include adjustment for maternal and pregnancycharacteristics in a large cohort of unaffected pregnancies. TheBPD measurement at 11 to 13weeks is simple and highlyreproducible and could be easily incorporated into the routinefirst trimester scan.

In conclusion, BPD values at 11 to 13weeks’ gestation arereduced in fetuses with holoprosencephaly. A smaller thanaverage BPD measurement in the first trimester could be analert to the presence of brain defect.

WHAT’S ALREADY KNOWN ABOUT THIS TOPIC?

• First trimester diagnosis of alobar holoprosencephaly is based onthe visualization of a single ventricle.

• Failure to identify the ‘butterfly sign’ at 11 to 13weeks is a warningsign.

• The detection rate in the first trimester is approximately 78%.

WHAT DOES THIS STUDY ADD?

• Biparietal diameter values at 11 to 13weeks were significantlysmaller. They were below the 5th centile in 32.4% of cases andbelow the 50th centile in 67.6%.

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