The Diagnostic Value Of Fetal Facial Indicators In Fetal Chromosomal Diseases In Early And Middle Pregnancy

Background and Purposes:Facial phenotype has good diagnostic reference value for many genetic diseases.Using three-dimensional ultrasound,multiple facial related indicators were measured,including the frontomaxillary facial（FMF）angle,the maxilla-nasion-mandible（MNM）angle,the inferior facial angle（IFA）,the facial maxillary angle（FMA）,and the frontal nasomental angle（FNMA）,to assess the characteristics of fetal facial development.We aim to initially establish the normal reference value range of normal fetuses in the Chinese population for the growth and development of fetal facial structure,and analyze the relationship between various indicators and gestational age（GA）.More importantly,study the diagnostic value of various fetal facial indicators for chromosome and genetic diseases.Methods:Underwent three-dimensional（3D）ultrasound,a total of 804 fetuses with normal ultrasound examinations and normal follow-up outcomes from 11 to 20⁺⁶ weeks of gestation in our hospital from December 2020 to February 2023 were included in the normal group.147 fetuses diagnosed as chromosomal abnormalities or genomic diseases through invasive prenatal diagnosis were included in the abnormal group,including 35 cases of trisomy 21 syndrome,32 cases of trisomy 18 syndrome,14 cases of trisomy 13 syndrome,15 cases of sex chromosome abnormalities,23 cases of other chromosomal abnormalities,19 cases of genomic diseases,and 9 cases of monogenic diseases.Use 3D ultrasound to analyze the fetal facial angles of normal fetuses at various gestational weeks:1.Establish prenatal ultrasound scanning standards for the median sagittal plane of normal fetuses during early and middle pregnancy.Standardize the definition and unify the measurement standards of each fetal facial angle（FMF,FNMA,IFA,FMA,MMF,MNM）which was measured by two experienced ultrasound physicians.30 samples were randomly selected from the first collected 200 samples,and intra-class correlation coefficient（ICC）was used to analyze the consistency between different measurements and between different measurements within the same measurement.Pearson correlation analysis was used to analyze the correlation between fetal facial parameters and gestational age（GA）.And established a regression equation.Study the diagnostic value of these normal fetal facial indicators for chromosomal and genetic diseases by receiver-operating characteristic curves（ROC）.Results:1.Consistency analysis:The fetal facial angles of 30 randomly selected normal samples were measured,including FMF,FNMA,IFA,FMA,MMF,and MNM.The internal ICC values of measurer 1 were 0.997,0.999,0.997,0.999,0.996,and 0.997respectively.The internal ICC values of measurer 2 were 0.998,0.999,0.996,0.999,0.996,and 0.998 respectively.The ICC values between different measurers were 0.764,0.520,0.939,0.731,0.752,and 0.834 respectively.The measurement of fetal facial angles within and between the measurers was consistent.2.The growth and development of various facial angles of normal fetuses during early and middle pregnancy are related to gestational age,the relationship equation of which conforms to a cubic polynomial:the measurement range of FMF angle is 52.56°to 115.89°,with a mean value of 83.16°±9.76°.FMF angle=2.17E2-23.88×GA+1.45×GA²-0.03×GA³（R²=0.113,P=0.000）,which is negatively correlated with gestational age.The measurement range of FNMA is 127.60°to 170.16°,with a mean value of 147.27°±8.15°,which is negatively correlated with gestational age.FNMA=5.81E2-77.69×GA+4.57×GA²-0.09×GA³（R²=0.262,P=0.000）,which is negatively correlated with gestational age.The measurement range of IFA is 44.26°to117.49°,with a mean value of 74.61°±11.66°,which is negatively correlated with gestational age.IFA=2.65E2-32.16×GA+1.83×GA²-0.04×GA³（R²=0.181,P=0.000）.The measurement range of FMA is 44.65°to 110.21°,with a mean value of70.43°±8.90°,which is negatively correlated with gestational age.FMA=1.95E2-21.21×GA+1.18×GA²-0.02×GA³（R²=0.037,P=0.000）.The measurement range of MMF angle is 59.26°to 126.64°,with a mean value of 92.62°±10.52°,which is negatively correlated with gestational age.MMF angle=3.95E2-52.65×GA+3.02×GA²-0.06×GA³（R²=0.181,P=0.000）;The measurement range of MNM angle is 0.12°to19.37°,with a mean value of 8.27°±4.41°,which is positively correlated with gestational age.MNM angle=11.65-1.68×GA+0.14×GA²-2.65E-3×GA³（R²=0.142,P=0.000）.3.The mean ranges of FMF angle in fetuses of trisomy 21 syndrome,sex chromosome abnormalities,other chromosome abnormalities,and genomic diseases were 76.03°±7.51°（Z=-1.204,P<0.05）,76.91°±7.89°（Z=-2.220,P<0.05）,79.40°±10.37°（Z=-2.030,P<0.05）,and 77.55°±10.34°（Z=-2.066,P<0.05）,respectively,which were significantly smaller than that of normal fetuses.The mean ranges of FNMA in fetuses of other chromosomal abnormalities and genomic diseases were 143.25°±6.59°（Z=-1.980,P<0.05）and 141.79°±7.62°（Z=-3.902,P<0.05）,respectively,which were significantly smaller than those of normal fetuses;The mean ranges of IFA in fetuses of trisomy 21 syndrome,trisomy 18 syndrome,trisomy 13 syndrome,other chromosomal abnormalities,and genomic diseases were66.23°±11.44°（Z=-3.847,P<0.05）,63.23°±11.89°（Z=-4.628,P<0.05）,56.74°±16.11°（Z=-3.927,P<0.05）,65.29°±10.65°（Z=-3.892,P<0.05）,and 66.12°±5.25°（Z=-3.541,P<0.05）,respectively,which were significantly smaller than that of normal fetuses.The mean range of FMA in fetuses with trisomy 13 syndrome was 55.81°±17.69°（Z=-3.672,P<0.05）,which was significantly smaller than that of fetuses in the normal group.The mean ranges of MMF angles in fetuses with trisomy 21 syndrome,trisomy 18syndrome,trisomy 13 syndrome,sex chromosome abnormalities,other chromosome abnormalities,and genomic diseases were 82.26°±14.50°（Z=-3.882,P<0.05）,71.95°±10.14°（Z=-3.943,P<0.05）,85.05°±10.06°（Z=-2.660,P<0.05）,87.10°±8.72°（Z=-2.529,P<0.05）,and 80.15°±12.21°（Z=-4.160,P<0.05）,respectively,which were smaller than that of fetuses in the normal group,which were statistically significant.There was no statistically significant difference in MNM angle between fetuses with trisomy 21 syndrome,trisomy 18 syndrome,trisomy 13 syndrome,sexual chromosome abnormalities,other chromosome abnormalities,genomic diseases,and monogenic diseases compared to normal fetuses（P=0.815,P=0.452,P=0.069,P=0.322,P=0.051,P=0.887,P=0.614）.During early and middle pregnancy,FMA has the highest sensitivity for trisomy13 syndrome（98.2%）,followed by IFA,FMA,and MMF angle（95.3%,86.7%,and83.3%）.When FMA is less than 61.29°or IFA is less than 56.67°,trisomy 13 syndrome should be highly suspected,and we should be alert to the presence of small mandible or cleft lip and palate.The detection rate of genomic diseases by FNMA was 96.0%;The sensitivity of IFA to trisomy 13 syndrome and monogenic diseases was 95.5%,followed by other chromosomal abnormalities（74.2%）,trisomy 18 syndrome（71.7%）,and genomic diseases（64%）;The sensitivity of FMA for trisomy 13 syndrome was86.6%;The sensitivity of MMF angle to trisomy 13 syndrome was 83.1%,followed by genomic diseases（78.7%）,trisomy 18 syndrome（71.4%）,and sex chromosome abnormalities（71.3%）.The sensitivity of multiple indicators combined screening for trisomy 21 syndrome is 83%,which is higher than the accuracy of independent indicator screening,but has no significant effect on improving the detection of other abnormal diseases.Conclusions:1.During early and middle pregnancy,various fetal facial measurement indicators have good repeatability,which is feasible in clinical work.2.The normal reference ranges of fetal various measurement indicators during early and middle pregnancy in Chinese population were obtained through large sample data,and there was a good correlation between each indicator and gestational age.3.FMF angle,FNMA,IFA,FMA,and MMF angle are reliable independent indicators for screening for trisomy 13 syndrome,and also can be used as sensitive indicators to indicate cleft lip and palate and small mandible;The combined screening of multiple indicators during early and middle pregnancy has certain diagnostic significance for the detection of trisomy 21 syndrome;Fetal facial structure indicators have certain significance in the detection of other chromosomal abnormalities,genomic diseases,or monogenic diseases during early and middle pregnancy;MNM angle is not the best ultrasound marker for early and middle pregnancy to indicate trisomy 21 syndrome,trisomy 18syndrome,trisomy 13 syndrome,other chromosomal abnormalities,genomic diseases,and monogenic diseases.