Diagnosis of fetal β-Thalassemia by noninvasive prenatal testing combined with serum soluble transferrin receptor, growth differentiation factor-15 and red blood cell volume distribution width coefficient of variation of pregnant women

doi:10.3877/cma.j.issn.1673-5250.2019.06.016

Objective

To investigate the diagnostic values of noninvasive prenatal testing (NIPT) combined with serum soluble transferrin receptor (sTfR), growth differentiation factor (GDF)-15, and red blood cell volume distribution coefficient of variation (RDW-CV) in pregnant women for diagnosis of fetal β-Thalassemia.

Methods

From January 2017 to June 2018, a total of 120 pregnant women whose fetuses were diagnosed as β-Thalassemia by amniocentesis in Zigong Maternal and Child Health Hospital were selected as research subjects. They were included into mild group (n=48), intermediate group (n=40) and severe group (n=32), respectively, according to mild, intermediate and severe β-Thalassemia of their fetuses. And other 100 cases healthy pregnant women who received routinely prenatally examination in the same hospital during the same period and with normal development of fetuses were selected as controls, and were included into control group. Fasting elbow venous blood was collected from 4 groups of fetal pregnant women, and fetal cell-free DNA (cfDNA) was collected from peripheral plasma of pregnant women. After amplification of cfDNA by twice PCR methods, fetal β-Thalassemia gene was detected by reverse dot blot hybridization. Enzyme-linked immunosorbent assay method was used to detect serum levels of sTfR, GDF-15 and RDW-CV of pregnant women in 4 groups. Serum levels of sTfR, GDF-15 and RDW-CV of pregnant women in 4 groups were compared by one-way ANOVA, and further multiple comparisons were performed by least significant difference (LSD)-t test. The sensitivity, specificity, crude accuracy, positive predictive value, and negative predictive value of combination of NIPT and serum sTfR, GDF-15 and RDW-CV levels of pregnant women, and detection of these four indicators alone for the diagnosis of fetal β-Thalassemia were calculated by comparison with " gold standard" of fetal β-Thalassemia. The procedures in this study were in line with the requirements of World Medical Association Declaration of Helsinki revised in 2013. There were no statistical differences in general clinical data such as fetal gestational age and age of pregnant women among four groups (P>0.05).

Results

①Among 40 pregnant women who had the same genotype of β-Thalassemia with her husband, diagnosis accordance rate of NIPT and prenatal diagnosis amniocentesis for diagnosis of fetal β-Thalassemia was 90.0% (36/40). And among 80 pregnant women who had different β-Thalassemia genotype with her husband, diagnosis accordance rate of these two methods was 90.0% (72/80). ②The serum levels of sTfR, GDF-15, and RDW-CV of pregnant women in four groups were compared, and all the differences were statistically significant (F=2 283.445, 323.181, 45.900, Pall<0.001). Results of further multiple comparisons showed that there were statistically significant differences in serum levels of sTfR, GDF-15, and RDW-CV of pregnant women between each two groups (P<0.05), and serum levels of sTfR, GDF-15, and RDW-CV of pregnant women gradually increased with the increase of fetal β-Thalassemia severity. ③The sensitivity, specificity, crude accuracy, positive predictive value, and negative predictive value for diagnosis of fetal β-Thalassemia by NIPT combined with serum levels of sTfR, GDF-15, and RDW-CV of pregnant women were 86.7%, 88.0%, 87.3%, 86.7% and 84.6%, respectively. And its specificity and positive predictive value were significantly higher than those of serum sTfR, GDF-15, and RDW-CV levels detection alone in pregnant women, and all the differences were statistically significant (vs serum sTfR level detection in pregnant women: χ²=8.866, 5.301, P=0.003, 0.021; vs serum GDF-15 level detection in pregnant women: χ²=9.765, 5.929, P=0.002, 0.015; vs serum RDW-CV level detection in pregnant women: χ²=7.167, 4.327, P=0.007, 0.038).

Conclusions

Serum level of sTfR, GDF-15 and RDW-CV of pregnant women are expected to be the diagnostic markers of fetal β-Thalassemia. NIPT combined with detection of these three indicators can improve the specificity and positive predictive value for diagnosis of fetal β-Thalassemia. As the sample size in this study is relatively small, the diagnostic value of NIPT combined with serum levels of sTfR, GDF-15 and RDW-CV of pregnant women for fetal β-Thalassemia remains to be further studied and confirmed.

Key words: beta-Thalassemia, Prenatal diagnosis, Noninvasive prenatal testing, Receptors, transferrin, Growth differentiation factors, Red blood cell volume distribution width coefficient of variation, Biological markers, Fetus, Pregnant women

表1 β-珠蛋白基因PCR扩增引物序列及其产物长度

引物名称	引物序列	扩增产物长度(bp)
Beta1-F	5′-GCCAATCTACTCCCAGGA-3′	245
Beta1-R	5′-ACCTGTCTTGTAACCTTGA-3′	245
Beta2-F	5′-CTCTTGGGTTTCTGATAGG-3′	216
Beta2-R	5′-TGAGGTTGTCCAGGTGAG-3′	216
Beta3-F	5′-TGCCTCTTTGCACCATTC-3′	181
Beta3-R	5′-CAGCCTTATCCCAACCAT-3′	181

表1 β-珠蛋白基因PCR扩增引物序列及其产物长度

引物名称	引物序列	扩增产物长度(bp)
Beta1-F	5′-GCCAATCTACTCCCAGGA-3′	245
Beta1-R	5′-ACCTGTCTTGTAACCTTGA-3′	245
Beta2-F	5′-CTCTTGGGTTTCTGATAGG-3′	216
Beta2-R	5′-TGAGGTTGTCCAGGTGAG-3′	216
Beta3-F	5′-TGCCTCTTTGCACCATTC-3′	181
Beta3-R	5′-CAGCCTTATCCCAACCAT-3′	181

表2 妊娠胎儿β-地中海贫血的NIPT结果与羊膜腔穿刺术结果不一致的12例孕妇中，受试者夫妻双方β-地中海贫血基因型及其羊膜腔穿刺术与NIPT诊断的胎儿β-地中海贫血基因型分析

孕妇编号(No.)	孕妇β-地中海贫血基因型	孕妇丈夫β-地中海贫血基因型	羊膜腔穿刺术的胎儿β-地中海贫血基因型	NIPT诊断的胎儿β-地中海贫血基因型
1	654M/N	654M/N	654M/N	N/N
2	17M/N	17M/N	17M/N	N/N
3	－28M/N	－28M/N	－28M/N	N/N
4	41-42M/N	41-42M/N	41-42M/N	N/N
5	17M/N	41-42M/N	41-42M/N	17M/N
6	71-72M/N	41-42M/N	41-42M/N	71-72M
7	41-42M/N	N/N	41-42M/N	N/N
8	17M/N	－29M/N	17M/N	－29M/N
9	654M/N	41-42M/N	654M/N	41-42M/N
10	－28M/N	17M/N	17M/N	－28M/N
11	17M/N	－29M/N	－29M/N	17M/N
12	17M/N	654M/N	654M/N	17M/N

孕妇编号(No.)	孕妇β-地中海贫血基因型	孕妇丈夫β-地中海贫血基因型	羊膜腔穿刺术的胎儿β-地中海贫血基因型	NIPT诊断的胎儿β-地中海贫血基因型
1	654M/N	654M/N	654M/N	N/N
2	17M/N	17M/N	17M/N	N/N
3	－28M/N	－28M/N	－28M/N	N/N
4	41-42M/N	41-42M/N	41-42M/N	N/N
5	17M/N	41-42M/N	41-42M/N	17M/N
6	71-72M/N	41-42M/N	41-42M/N	71-72M
7	41-42M/N	N/N	41-42M/N	N/N
8	17M/N	－29M/N	17M/N	－29M/N
9	654M/N	41-42M/N	654M/N	41-42M/N
10	－28M/N	17M/N	17M/N	－28M/N
11	17M/N	－29M/N	－29M/N	17M/N
12	17M/N	654M/N	654M/N	17M/N

表3 4组孕妇血清sTfR、GDF-15、RDW-CV水平比较(±s)

组别		例数	血清sTfR水平(mg/mL)	血清GDF-15水平(ng/mL)	血清RDW-CV水平(%)
轻型组		48	205.8±15.4	29.9±5.0	21.0±9.2
中型组		40	223.8±15.6	33.5±5.0	23.7±9.1
重型组		32	230.1±16.1	38.1±5.2	28.2±9.3
对照组		100	75.8±8.2	15.5±3.4	13.7±2.1
总体比较		?	?	?	?
?	F值	?	2 283.445	323.181	45.900
?	P值	?	<0.001	<0.001	<0.001
轻型组vs中型组		?	?	?	?
?	LSD-t值	?	5.428	3.363	1.983
?	P值	?	<0.001	0.001	0.045
轻型组vs重型组		?	?	?	?
?	LSD-t值	?	7.684	5.784	4.651
?	P值	?	<0.001	<0.001	<0.001
轻型组vs对照组		?	?	?	?
?	LSD-t值	?	67.044	18.283	7.176
?	P值	?	<0.001	<0.001	<0.001
中型组vs重型组		?	?	?	?
?	LSD-t值	?	4.238	4.765	5.173
?	P值	?	<0.001	<0.001	<0.001
中型组vs对照组		?	?	?	?
?	LSD-t值	?	75.438	26.973	13.127
?	P值	?	<0.001	<0.001	<0.001
重型组vs对照组		?	?	?	?
?	LSD-t值	?	87.563	33.231	22.176
?	P值	?	<0.001	<0.001	<0.001

表3 4组孕妇血清sTfR、GDF-15、RDW-CV水平比较(±s)

组别		例数	血清sTfR水平(mg/mL)	血清GDF-15水平(ng/mL)	血清RDW-CV水平(%)
轻型组		48	205.8±15.4	29.9±5.0	21.0±9.2
中型组		40	223.8±15.6	33.5±5.0	23.7±9.1
重型组		32	230.1±16.1	38.1±5.2	28.2±9.3
对照组		100	75.8±8.2	15.5±3.4	13.7±2.1
总体比较		?	?	?	?
?	F值	?	2 283.445	323.181	45.900
?	P值	?	<0.001	<0.001	<0.001
轻型组vs中型组		?	?	?	?
?	LSD-t值	?	5.428	3.363	1.983
?	P值	?	<0.001	0.001	0.045
轻型组vs重型组		?	?	?	?
?	LSD-t值	?	7.684	5.784	4.651
?	P值	?	<0.001	<0.001	<0.001
轻型组vs对照组		?	?	?	?
?	LSD-t值	?	67.044	18.283	7.176
?	P值	?	<0.001	<0.001	<0.001
中型组vs重型组		?	?	?	?
?	LSD-t值	?	4.238	4.765	5.173
?	P值	?	<0.001	<0.001	<0.001
中型组vs对照组		?	?	?	?
?	LSD-t值	?	75.438	26.973	13.127
?	P值	?	<0.001	<0.001	<0.001
重型组vs对照组		?	?	?	?
?	LSD-t值	?	87.563	33.231	22.176
?	P值	?	<0.001	<0.001	<0.001

表4 NIPT与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

NIPT	β-地中海贫血诊断"金标准"^a		合计
NIPT	＋	－	合计
＋	109	22	131
－	11	78	89
合计	120	100	220

表4 NIPT与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

NIPT	β-地中海贫血诊断"金标准"^a		合计
NIPT	＋	－	合计
＋	109	22	131
－	11	78	89
合计	120	100	220

表5 孕妇血清sTfR水平检测与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

孕妇血清sTfR水平检测	β-地中海贫血诊断"金标准"^a		合计
孕妇血清sTfR水平检测	＋	－	合计
＋	109	29	138
－	11	71	82
合计	120	100	220

表5 孕妇血清sTfR水平检测与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

孕妇血清sTfR水平检测	β-地中海贫血诊断"金标准"^a		合计
孕妇血清sTfR水平检测	＋	－	合计
＋	109	29	138
－	11	71	82
合计	120	100	220

表6 孕妇血清GDF-15水平检测与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

孕妇血清GDF-15水平检测	β-地中海贫血诊断"金标准"^a		合计
孕妇血清GDF-15水平检测	＋	－	合计
＋	108	30	138
－	12	70	82
合计	120	100	220

表6 孕妇血清GDF-15水平检测与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

孕妇血清GDF-15水平检测	β-地中海贫血诊断"金标准"^a		合计
孕妇血清GDF-15水平检测	＋	－	合计
＋	108	30	138
－	12	70	82
合计	120	100	220

表7 孕妇血清RDW-CV水平检测与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

孕妇血清RDW-CV水平检测	β-地中海贫血诊断"金标准"^a		合计
孕妇血清RDW-CV水平检测	＋	－	合计
＋	109	27	136
－	11	73	84
合计	120	100	220

表7 孕妇血清RDW-CV水平检测与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

孕妇血清RDW-CV水平检测	β-地中海贫血诊断"金标准"^a		合计
孕妇血清RDW-CV水平检测	＋	－	合计
＋	109	27	136
－	11	73	84
合计	120	100	220

表8 NIPT联合孕妇血清sTfR、GDF-15、RDW-CV水平检测与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

联合检测	β-地中海贫血诊断"金标准"^a		合计
联合检测	＋	－	合计
＋	104	12	116
－	16	88	104
合计	120	100	220

表8 NIPT联合孕妇血清sTfR、GDF-15、RDW-CV水平检测与β-地中海贫血诊断"金标准"对220例孕妇妊娠胎儿的β-地中海贫血诊断结果比较(例)

联合检测	β-地中海贫血诊断"金标准"^a		合计
联合检测	＋	－	合计
＋	104	12	116
－	16	88	104
合计	120	100	220

表9 NIPT与孕妇血清sTfR、GDF-15、RDW-CV水平单独检测及联合检测，对于胎儿β-地中海贫血的诊断价值比较

检测项目		敏感度(%)	特异度(%)	粗符合率(%)	阳性预测值(%)	阴性预测值(%)
NIPT		90.8	78.0	85.0	83.2	87.6
孕妇血清sTfR水平检测		90.8	71.0	81.8	79.0	86.6
孕妇血清GDF-15水平检测		90.0	70.0	80.9	78.3	85.4
孕妇血清RDW-CV水平检测		90.8	73.0	82.7	80.1	86.9
联合检测		86.7	88.0	87.3	86.7	84.6
联合检测vs NIPT		?	?	?	?	?
?	χ²值	1.403	3.545	0.476	2.156	0.365
?	P值	0.307	0.060	0.490	0.142	0.546
联合检测vs孕妇血清sTfR水平检测		?	?	?	?	?
?	χ²值	1.043	8.866	2.505	5.301	0.143
?	P值	0.307	0.003	0.114	0.021	0.705
联合检测vs孕妇血清GDF-15水平检测		?	?	?	?	?
?	χ²值	0.647	9.765	3.330	5.929	0.020
?	P值	0.421	0.002	0.068	0.015	0.887
联合检测vs孕妇血清RDW-CV水平检测		?	?	?	?	?
?	χ²值	1.403	7.167	1.783	4.327	0.198
?	P值	0.307	0.007	0.182	0.038	0.656

表9 NIPT与孕妇血清sTfR、GDF-15、RDW-CV水平单独检测及联合检测，对于胎儿β-地中海贫血的诊断价值比较

检测项目		敏感度(%)	特异度(%)	粗符合率(%)	阳性预测值(%)	阴性预测值(%)
NIPT		90.8	78.0	85.0	83.2	87.6
孕妇血清sTfR水平检测		90.8	71.0	81.8	79.0	86.6
孕妇血清GDF-15水平检测		90.0	70.0	80.9	78.3	85.4
孕妇血清RDW-CV水平检测		90.8	73.0	82.7	80.1	86.9
联合检测		86.7	88.0	87.3	86.7	84.6
联合检测vs NIPT		?	?	?	?	?
?	χ²值	1.403	3.545	0.476	2.156	0.365
?	P值	0.307	0.060	0.490	0.142	0.546
联合检测vs孕妇血清sTfR水平检测		?	?	?	?	?
?	χ²值	1.043	8.866	2.505	5.301	0.143
?	P值	0.307	0.003	0.114	0.021	0.705
联合检测vs孕妇血清GDF-15水平检测		?	?	?	?	?
?	χ²值	0.647	9.765	3.330	5.929	0.020
?	P值	0.421	0.002	0.068	0.015	0.887
联合检测vs孕妇血清RDW-CV水平检测		?	?	?	?	?
?	χ²值	1.403	7.167	1.783	4.327	0.198
?	P值	0.307	0.007	0.182	0.038	0.656

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