Screening Cut-off Value of 17- hydroxyprogesterone for Neonatal Congenital Adrenal Hyperplasia
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摘要:
目的 分析不同性别、胎龄、采血日龄、出生体重对17-羟孕酮（17-hydroxyprogesterone，17-OHP）浓度的影响，制定适合实验室自身的新生儿先天性肾上腺皮质增生症（congenital adrenal hyperplasia，CAH）筛查阳性切值。 方法 收集2019年9月至2024年10月昆明医科大学第一附属医院新生儿遗传代谢病筛查中心共52 836例CAH筛查样本，采用时间分辨荧光免疫分析法检测17-OHP浓度，采用Mann-Whitney U 检验、Kruskal-Wallis H检验比较不同性别、出生体重、胎龄和采血日龄等特征的新生儿17-OHP浓度，率的比较采用多组率卡方检验和Fisher确切概率法，多元线性回归分析各临床特征与17-OHP浓度的关系，以99.5%百分位数为17-OHP筛查阳性切值。 结果 男性新生儿17-OHP浓度高于女性新生儿，差异有统计学意义（Z= -17.768，P < 0.05）。分别比较不同胎龄、不同出生体重、不同采血日龄的新生儿17-OHP浓度，差异有统计学意义（χ2分别为 5235.187 、3682.665 、493.414，P值均=0.00）。进一步两两比较，除采血日龄≥3 d且<4 d和≥4 d且<7 d新生儿17-OHP浓度差异无统计学意义外（Z= -0.950，P = 0.342），其余不同孕周、胎龄和采血日龄新生儿17-OHP浓度差异均有统计学意义（P < 0.05）。新生儿17-OHP浓度随胎龄和出生体重增加而下降。不同胎龄、不同出生体重、不同采血日龄组17-OHP初筛阳性率、筛查阳性率差异均有统计学意义（P < 0.05），且随胎龄、出生体重、采血日龄的增加而下降。多元线性回归结果表明，17-OHP浓度与多个因素有关，按作用从大到小依次为胎龄、出生体重、采血日龄、性别。结论 应综合考虑多种因素对新生儿末梢血17-OHP浓度的影响，将昆明医科大学第一附属医院新筛中心CAH筛查17-OHP阳性切值修改为：正常体重足月新生儿≥14.00 nmol/L，早产或（和）低体重新生儿≥36.00 nmol/L，以提高新生儿CAH筛查的特异度，减少假阳性。 -
关键词:
- 新生儿遗传代谢病筛查 /
- 先天性肾上腺皮质增生症 /
- 17-羟孕酮 /
- 筛查切值
Abstract:Objective To analyze the effects of different gender, gestational age, birth weight and blood collection date on the value of 17-hydroxyprogesterone （17-OHP） in neonatal screening for congenital adrenal hyperplasia （CAH） and to develop a positive cut-off for CAH screening that is appropriate for the laboratory itself. Methods Time-resolved fluorescence immunoassay was used to detect 17-OHP concentration, and Mann-Whitney U test and Kruskal-Wallis H test were used to compare 17-OHP concentration of newborns with the different gender, birth weight, gestational age and blood collection age. The comparison of rates was conducted using the multi-set rate chi-square test and Fisher's exact probability method. The relationship between the clinical features and 17-OHP concentration was analyzed by multiple linear regression, and the cut-off value of 17-OHP screening was 99.5% percentile. Results The 17-OHP concentration of male neonates was higher than that of female neonates, and the difference was statistically significant （Z= -17.768, P < 0.05）. The 17-OHP concentration of neonates in groups with different gestational age, different birth weight, and different blood collection days were compared respectively, and the difference was statistically significant （χ2= 5235.187 、3682.665 、493.414 respectively, P = 0.00）. Further pair comparison showed that there were statistically significant differences in 17-OHP concentration of neonates at different gestational weeks, gestational age and blood collection days （P < 0.05）, except that age of blood collection ≥3 and <4 days and ≥4 and <7 days（Z= -0.950, P = 0.342）. Neonatal 17-OHP concentration decreased with the gestational age and birth weight increase. There were statistically significant differences in the initial screening positive rate and screening positive rate of 17-OHP among different gestational ages and different birth weights groups (P < 0.05), and they decreased with the increase of gestational age, birth weight and age at the time of blood collection. The results of multiple linear regression showed that 17-OHP concentration was related to the several factors, including the gestational age, birth weight, age of blood collection and gender in descending order.Conclusion The effects of various factors on the concentration of 17-OHP in neonatal peripheral blood should be comprehensively considered. The cut-off value of 17-OHP for CAH screening in the Screening Center for Neonatal Genetic Metabolic Diseases in the First Affiliated Hospital of Kunming Medical University is modified to ≥14.00 nmol/L for full-term neonates of normal weight and ≥36.00 nmol/L for premature or/and low-weight neonates so as to improve the specificity of neonatal CAH screening and reduce the false positives. -
表 1 不同组别新生儿末梢血 17-OHP浓度（nmol/L）
Table 1. Neonatal peripheral blood 17-OHP concentration in different groups （nmol/L）
组别 n 几何均数 百分位数 Z P P25 P50 P75 P99.5 性别 女 25 267 3.19 2.33 3.32 5.00 25.17 −17.768 <0.001* 男 27 569 3.30 2.54 3.64 5.50 28.52 超早产组 87 17.31 9.24 16.60 34.30 — −2.442a 0.015* 极早产组 477 12.75 8.38 13.50 21.15 88.70 −3.162 a 0.002* 中期早产组 581 11.12 7.51 11.40 17.55 63.36 −15.760 a <0.001* 晚期早产组 3059 6.81 4.43 7.02 10.40 36.46 −55.799 a <0.001* 足月儿组 48490 3.38 2.38 3.34 4.85 14.20 −5.169 a <0.001* 过期产儿组 142 2.62 1.92 2.64 3.79 — 极低出生体重组 536 11.34 8.69 13.55 21.00 171.45 −21.108b <0.001* 低出生体重组 4220 4.51 3.57 6.11 9.93 50.18 −49.792b <0.001* 正常出生体重组 46748 3.36 2.39 3.37 4.92 15.30 −9.028 b <0.001* 巨大儿组 1332 2.54 2.11 3.00 4.18 11.93 采血日龄（d） ≥3且<4 15732 3.25 2.40 3.37 5.03 30.00 −0.950c 0.342 ≥4且<7 29163 3.66 2.38 3.41 5.12 26.10 −21.029 c <0.001* ≥7 7941 5.07 2.78 4.07 6.07 24.47 注：GA：胎龄；BW：出生体重；a非参数Mann-Whitney U 检验，与下一组较大胎龄组比较；b非参数Mann-Whitney U 检验，与下一组较大出生体重组比较；c非参数Mann-Whitney U 检验，与下一组较大采血日龄组比较；“-”表示无此值；*P < 0.05。 
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表 2 不同组别17-OHP初筛阳性率及筛查阳性率比较 [n（%）]
Table 2. Comparison of the initial screening positive rate and screening positive rate of 17-OHP in different groups [n（%）]
组别 筛查数 初筛阳性率 χ2 P 筛查阳性率 χ2 P 性别 女 25267 253（1.00） 5.836 0.016* 37（0.15） 0.069 0.793 男 27569 337（1.22） 38（0.14） 超早产组 87 27（31.03） 2994.493 <0.001* 3（3.45） 176.932 <0.001* 极早产组 477 87（18.24） 6（1.26） 中期早产组 581 82（14.11） 7（1.20） 晚期早产组 3059 72（2.35） 8（0.26） 足月儿组 48490 322（0.66） 51（0.11） 过期产儿组 142 0 0 极低出生体重组 536 117（21.83） 2277.615 <0.001* 5（0.93） 23.408 <0.001* 低出生体重组 4220 168（3.98） 21（0.50） 正常出生体重组 46748 300（0.64） 49（0.10 巨大儿组 1332 5（0.38） 0 采血日龄（d） ≥3且<4 15732 243（1.54） 65.589 <0.001* 28（0.18） 6.201 0.045* ≥4且<7 29163 317（1.09） 43（0.15） ≥7 7941 30（0.38） 4（0.05） *P < 0.05。
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表 3 新生儿末梢血17-OHP浓度影响因素的多元线性回归分析结果
Table 3. Results of multiple linear regression analysis of influencing factors of neonatal peripheral blood 17-OHP concentration
变量 未标准化系数 标准化系数 t P B Sb β 胎龄 −4.033 0.071 −0.295 −56.781 <0.001* 出生体重 −1.316 0.085 −0.081 −15.505 <0.001* 采血日龄 0.145 0.038 0.016 3.816 <0.001* 性别 0.360 0.050 0.029 7.211 <0.001* *P < 0.05。
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