Abstract
目的
探讨正常妊娠女性和子痫前期患者中性粒细胞/淋巴细胞比值（neutrophil-to-lymphocyte ratio, NLR）与血小板/淋巴细胞比值（platelet-to-lymphocyte, PLR）的变化以及孕早期NLR 和PLR预测子痫前期的价值。
方法
收集2016年1月1日–12月31日在四川大学华西第二医院住院分娩的485名孕妇（97例子痫前期、388例正常妊娠）及同期体检的30例正常非妊娠妇女的临床资料，计算并比较其NLR和PLR值。采用logistic回归分析子痫前期的危险因素，采用受试者工作特征曲线评估孕早期NLR和PLR对子痫前期的预测价值。
结果
在孕早、中、晚期，子痫前期组与正常妊娠组的NLR、PLR差异均无统计学意义。与正常非妊娠组相比，子痫前期组和正常妊娠组NLR从孕早期开始升高，孕中期达到最大值，孕晚期下降；PLR从孕中期开始降低，孕晚期达到最低水平，差异均有统计学意义（P<0.05）。在各个孕期，NLR和PLR与子痫前期严重程度、孕妇年龄和孕前体质量指数均无关。孕前肥胖、高龄和初产因素的联合模型预测子痫前期的曲线下面积（AUC）为0.84。孕早期NLR、孕早期PLR分别加入上述模型后的AUC均为0.85。
结论
NLR和PLR不是子痫前期的独立影响因素，不能提高对子痫前期的预测价值。
Keywords: 子痫前期, 中性粒细胞/淋巴细胞比值, 血小板/淋巴细胞比值, 预测, 炎症
Abstract
Objective
To investigate the changes of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in women with normal pregnancy women and pregnant women with preeclampsia (PE) and the value of using NLR and PLR in the first trimester to predict PE.
Methods
We retrospectively collected the clinical data of 485 pregnant women (97 had PE and 388 were of normal pregnancy) who were admitted to West China Second University Hospital and had their babies delivered there between January 1 and December 31, 2016 and 30 healthy women who were not pregnant and who had physical examination at the hospital over the same period. The subjects' NLR and PLR were calculated and compared. Logistic regression analysis was done to study the risk factors of PE, and the receiver operating characteristic curves were used to assess the value of using NLR and PLR in the first trimester to predict PE.
Results
There was no significant difference in NLR or PLR between the PE group and the normal pregnancy group in the first, second and third trimesters. Compared with that of the normal non-pregnant group, the NLR of the PE group and the normal pregnancy group started to rise in the first trimester, reached the maximum in the second trimester, and decreased in the third trimester; PLR started to decrease in the second trimester and reached the lowest level in the third trimester, exhibiting significant differences (P<0.05). In the three trimesters, NLR and PLR were not associated with the severity of PE, maternal age, or pre-pregnancy BMI. The predictive model combining factors including pre-pregnancy obesity, advanced maternal age, and nulliparity showed an area under the curve (AUC) of 0.84 for predicting PE. When NLR in the first trimester or PLR in the first trimester were added to the combined model of pre-pregnancy obesity, advanced maternal age, and nulliparity, the AUC subsequently derived were both 0.85.
Conclusion
NLR and PLR are not independent influencing factors of PE and cannot improve the predictive value for PE.
Keywords: Preeclampsia, Neutrophil-to-lymphocyte ratio, Platelet-to-lymphocyte ratio, Prediction, Inflammation
子痫前期（preeclampsia, PE）是妊娠期特有疾病，以妊娠20周后血压升高和/或蛋白尿为主要临床表现[1]，是孕产妇和围产儿发病率和死亡率升高的主要原因[2]。迄今为止，除了及时终止妊娠，子痫前期没有有效的治疗方法。因此，识别子痫前期的高危因素、早期筛查并及时防治是改善子痫前期患者围产结局的关键。近年来，中性粒细胞/淋巴细胞比（neutrophil-to-lymphocyte ratio, NLR）和血小板/淋巴细胞比（platelet-to-lymphocyte ratio, PLR）已作为肿瘤、心脏病和妊娠相关疾病的全身炎症标志物，并用于评估这些疾病的发病风险[3-6]。正常妊娠存在轻微炎症反应[7-8]，子痫前期与母体过度炎症反应有关[9]。外周血NLR和PLR是简单易得的炎症指标，然而利用NLR和PLR评估子痫前期和正常妊娠炎症状态的报道较少。近期研究报道了正常妊娠和子痫前期之间NLR和PLR的差异，但结果却不统一[10-11]。有学者发现[10]，子痫前期患者NLR和PLR值均显著高于正常妊娠女性，且孕早期NLR和PLR可有效预测子痫前期；其他学者却未发现子痫前期患者和正常妊娠女性之间NLR和PLR的差异[11]。鉴于此，本研究拟探讨子痫前期患者和正常妊娠女性NLR和PLR的变化，并评估孕早期NLR和PLR对子痫前期的预测价值。
1. 资料与方法
1.1. 一般资料
本研究获四川大学华西第二医院医学伦理委员会批准，批准号：医学科研2019伦审批第032号。重度或非重度子痫前期的诊断参照2015年《中国妊娠期高血压疾病诊治指南》[12]。纳入标准：子痫前期患者与正常妊娠女性需同时具备孕早、中、晚期血常规资料；正常妊娠女性孕期无内外科合并症及妊娠期并发症；正常非妊娠女性无内外科合并症。排除标准：①双胎及以上妊娠；②胎儿畸形；③孕前有高血压、糖尿病、肝肾功能异常、甲状腺功能异常、恶性肿瘤、心脏病、血液系统疾病病史。
按上述标准，回顾性纳入2016年1月1日–2016年12月31日在四川大学华西第二医院住院并分娩的子痫前期患者97例（其中重度子痫前期组57例，非重度子痫前期亚组40例）、正常妊娠女性388例（按病例组∶正常组1∶4的比例随机纳入），同期纳入正常非妊娠女性30例。根据中国成人超重和肥胖症预防与控制指南[13]，将妊娠女性分为正常体质量指数（BMI）组（BMI=18.5～23.9 kg/m2），低BMI组（BMI<18.5 kg/m2），超重组（BMI 24～27.9 kg/m2）和肥胖组（BMI≥28 kg/m2）。根据分娩年龄，分为高龄组（年龄≥35岁）和非高龄组（年龄<35岁）。
1.2. 资料收集及检测
孕妇的一般资料包括：年龄、教育程度、孕前BMI、是否吸烟/饮酒、孕次、产次、分娩孕周、分娩方式、血压以及孕早、中、晚期血常规数据，孕周以末次月经（月经规律者）或孕早期超声核实；新生儿资料包括：身长、体质量、性别、是否转入新生儿重症监护室；正常非妊娠女性资料包括：年龄、BMI、血常规。
在妊娠早、中、晚期分别采集血液样本5 mL，子痫前期患者在诊断明确时采集最后一次血液样本；正常非妊娠女性在体检时采集血液样本。血液样本用EDTA-K2抗凝剂处理，采用相同的自动分析仪（希森美康XN-2000，日本）检测外周血白细胞、中性粒细胞和血小板计数。NLR和PLR分别通过中性粒细胞计数或血小板计数除以淋巴细胞计数获得。
1.3. 孕早期NLR和PLR预测子痫前期
通过受试者工作特征（ROC）曲线评估孕早期NLR和PLR对子痫前期的预测价值。由于孕前肥胖、高龄、初产是子痫前期的危险因素，将孕早期NLR和PLR分别与孕前肥胖、高龄和初产因素纳入二元logistic回归分析，建立子痫前期预测模型。模型1联合孕早期NLR和孕前肥胖、高龄和初产因素，模型2联合孕早期PLR与孕前肥胖、高龄和初产因素，模型3是孕前肥胖、高龄和初产因素的联合。
1.4. 统计学方法
计量资料符合正态分布时以
表示，否则用中位数（四分位数间距）表示；计数资料以百分率（%）表示。对服从正态分布、具有方差齐性的计量资料两组间采用独立样本t检验；方差不齐时，采用近似t检验。对同一研究对象的同一指标在不同时间点的多次测量结果采用重复测量资料方差分析。分类变量资料采用卡方检验进行分析。以二元logistic回归分析孕早期NLR、PLR是否为子痫前期的高危因素，计算出OR值和95%CI。采用ROC曲线评估孕早期NLR、PLR及不同预测模型在子痫前期中的预测价值。计算约登指数最大切点对应的临界值、敏感性和特异性。计算ROC曲线下面积（AUC），以AUC<0.5为无预测价值，0.5～<0.7为预测准确性较低，0.7～0.9为预测准确性较好，>0.9为预测准确性高。α=0.05。
2. 结果
2.1. 一般资料
子痫前期组与正常妊娠组之间在年龄、血压、超重所占比例、教育水平（大学和研究生）和初产所占比例、分娩孕周、新生儿出生体质量和身长方面差异有统计学意义（P<0.05），而两组间高龄、低体质量和正常体质量及肥胖所占比例以及新生儿性别和转入新生儿重症监护室所占比例差异无统计学意义（表1）。
表 1. General clinical data of the of pregnant women.
孕妇的一般临床资料
| Baseline characteristic | Normal pregnant group (n=388) | Preeclampsia group (n=97) | P |
 or case (%). BMI: Body mass index; NICU: Neonatal intensive care unit. 1 mmHg=0.133 kPa. | |||
| Maternal age/yr. | 34.11±3.69 | 33.02±4.41 | 0.011 |
| ≥35 | 169 (33.84) | 35 (36.08) | 0.182 |
| Pre-pregnancy BMI/(kg/m2) | 21.67±2.56 | 22.66±3.35 | 0.002 |
| <18.5 | 36 (9.28) | 5 (5.16) | 0.18 |
| 18.5-23.9 | 280 (72.16) | 62 (63.92) | 0.11 |
| 24-27.9 | 62 (15.98) | 25 (25.77) | 0.025 |
| ≥28 | 10 (2.58) | 5 (5.15) | 0.325 |
| Level of education | |||
| Junior middle school or below | 12 (3.09) | 6 (6.19) | 0.195 |
| High school | 31 (7.99) | 3 (3.09) | 0.091 |
| Undergraduate | 256 (65.98) | 84 (86.60) | <0.001 |
| Postgraduate | 89 (22.94) | 4 (4.12) | <0.001 |
| Smoking or drinking status | 0 | 0 | － |
| Nulliparity | 12 (3.09) | 68 (70.1) | <0.001 |
| Delivery weeks/week | 39.02±2.23 | 38.42±1.78 | <0.001 |
| Admission systolic blood pressure/mmHg | 114.34±9.97 | 137.76±16.64 | <0.001 |
| Admission diastolic blood pressure/mmHg | 70.33±8.54 | 86.22±12.34 | <0.001 |
| Neonatal characteristics | |||
| Birth body mass/g | 3389.98±371.15 | 2954.33±705.36 | <0.001 |
| Body length/cm | 49.53±1.71 | 48.27±3.41 | <0.001 |
| Female | 187 (48.20) | 54 (55.70) | 0.188 |
| Admission to NICU | 20 (5.15) | 8 (8.25) | 0.243 |
2.2. 各组NLR、PLR比较
正常非妊娠组的NLR、PLR为健康对照女性的测值，以此为子痫前期组与正常妊娠组的基线对照值。在孕早、中、晚期，子痫前期组与正常妊娠组的NLR、PLR差异均无统计学意义。与基线对照值相比，子痫前期组和正常妊娠组NLR从孕早期开始升高，孕中期达到最大值，孕晚期下降；PLR从孕中期开始降低，孕晚期达到最低水平，差异均有统计学意义(P<0.05)（表2）。
表 2. Comparisons of the NLR and PLR among three groups.
研究对象的NLR和PLR值
| Variable | Pregnant stages | Normal pregnant group (n=388) | Preeclampsia group (n=97) |
| NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio. # The data of normal nonpregnant group (n=30) were shown as baseline control for normal pregnant group and preeclampsia group. * P<0.001, vs. baseline control. | |||
| NLR | Baseline control# | 2.47±0.79 | 2.47±0.79 |
| First trimester | 4.16±1.43* | 4.25±1.49* | |
| Second trimester | 4.52±1.42* | 4.44±1.52* | |
| Third trimester | 4.35±1.47* | 4.33±1.45* | |
| PLR | Baseline control# | 143.01±48.86 | 143.01±48.86 |
| First trimester | 128.48±42.30 | 125.58±47.21 | |
| Second trimester | 115.95±38.31* | 107.80±29.59* | |
| Third trimester | 107.63±38.54* | 102.19±28.02* | |
2.3. NLR和PLR与子痫前期严重程度的关系
在不同孕期，子痫前期组中重度和非重度子痫前期亚组之间NLR和PLR的差异均无统计学意义；即NLR和PLR与子痫前期严重程度无关（表3）。
表 3. Comparisons of the NLR and PLR between severe and non-severe preeclampsia cases.
重度和非重度子痫前期的NLR和PLR值
| Variable | Pregnant stages | Severe preeclampsia (n=57) | Non-severe preeclampsia (n=40) |
| NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio. | |||
| NLR | First trimester | 4.09±1.28 | 4.48±1.73 |
| Second trimester | 4.30±1.07 | 4.64±1.44 | |
| Third trimester | 3.67±1.09 | 3.99±1.21 | |
| PLR | First trimester | 124.34±33.27 | 127.35±62.38 |
| Second trimester | 112.74±34.17 | 111.31±38.58 | |
| Third trimester | 98.24±34.00 | 105.49±32.18 | |
2.4. NLR和PLR与孕妇年龄的关系
无论是在子痫前期组中还是在正常妊娠组中，两个年龄亚组在不同孕期的NLR、PLR的差异均无统计学意义；即NLR和PLR与孕妇年龄无关（表4）。
表 4. Comparisons of the NLR and PLR in different age sub-groups of preeclampsia and normal pregnant women.
子痫前期与正常妊娠女性不同年龄亚组NLR和PLR值
| Variable | Pregnant stages | Preeclampsia group | Normal pregnant group | |||
| ≥35 yr. (n=34) | <35 yr. (n=63) | ≥35 yr. (n=169) | <35 yr. (n=219) | |||
| NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio. | ||||||
| NLR | First trimester | 4.45±1.86 | 4.15±1.24 | 4.22±1.45 | 4.12±1.41 | |
| Second trimester | 4.63±1.63 | 4.33±1.45 | 4.48±1.61 | 4.56±1.24 | ||
| Third trimester | 4.62±1.53 | 4.17±1.38 | 4.28±1.43 | 4.41±1.50 | ||
| PLR | First trimester | 129.82±52.94 | 123.29±44.09 | 130.78±43.59 | 126.69±41.29 | |
| Second trimester | 105.45±34.22 | 109.07±26.99 | 114.03±38.91 | 117.43±37.86 | ||
| Third trimester | 101.28±31.72 | 102.69±26.06 | 104.02±34.25 | 110.42±41.41 | ||
2.5. NLR和PLR与孕前BMI的关系
无论是在子痫前期组中还是在正常妊娠组中，不同BMI亚组之间NLR、PLR的差异均无统计学意义；即NLR和PLR与孕前BMI无关（表5、表6）。
表 5. Comparisons of the NLR and PLR in different BMI sub-groups of normal pregnant women.
正常妊娠女性不同BMI亚组NLR和PLR值
| Variable | Pregnant stages | Normal BMI (n=282) | Low BMI (n=36) | High BMI (n=70) |
| NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio. Normal BMI: BMI=18.5-23.9 kg/m2; Low BMI: BMI<18.5 kg/m2; High BMI includs overweight (24-27.9 kg/m2) and obesity (BMI≥28 kg/m2). | ||||
| NLR | First trimester | 4.21±1.49 | 4.35±1.48 | 3.87±1.08 |
| Second trimester | 4.59±1.58 | 4.43±1.21 | 4.29±1.12 | |
| Third trimester | 4.56±1.58 | 4.35±1.53 | 4.56±1.58 | |
| PLR | First trimester | 129.08±43.79 | 135.96±42.53 | 122.21±35.24 |
| Second trimester | 115.80±39.54 | 113.49±32.14 | 111.77±28.65 | |
| Third trimester | 109.02±40.02 | 103.72±32.10 | 105.37±28.24 | |
表 6. Comparisons of the NLR and PLR in different BMI sub-groups of preeclampsia women.
子痫前期患者不同BMI亚组NLR和PLR值
| Variable | Pregnant stages | Normal BMI (n=62) | Low BMI (n=5) | High BMI (n=30) |
| NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio. Normal BMI: BMI=18.5-23.9 kg/m2; Low BMI: BMI<18.5 kg/m2; High BMI includs overweight (24-27.9 kg/m2) and obesity (BMI≥28 kg/m2). | ||||
| NLR | First trimester | 4.21±1.59 | 4.78±2.14 | 4.25±1.15 |
| Second trimester | 4.35±1.23 | 4.32±2.01 | 4.35±1.23 | |
| Third trimester | 3.77±1.17 | 3.47±1.30 | 3.77±1.17 | |
| PLR | First trimester | 126.57±44.62 | 117.51±46.45 | 124.88±53.65 |
| Second trimester | 107.54±32.95 | 102.52±45.06 | 123.27±38.78 | |
| Third trimester | 96.64±29.86 | 108.14±40.62 | 109.56±37.95 | |
2.6. 孕早期NLR和PLR预测子痫前期的价值
ROC曲线显示，孕早期NLR在正常妊娠女性和子痫前期患者之间预测子痫前期的AUC为0.53（95%CI，0.46～0.59），截断值为6.24时敏感性为52.0%、特异性为57.1%；孕早期PLR预测子痫前期的AUC为0.46（95%CI，0.40～0.53），截断值为125.00时敏感性为53.2%、特异性为35.4%（图1A）。
图 1.
ROC curves for predicting preeclampsia with NLR and PLR in the first trimester
孕早期NLR和PLR预测子痫前期的ROC曲线
A: ROC curves for NLR and PLR in the first trimester to predict preeclampsia; B: ROC curves for combined models to predict preeclampsia. Model 1 is a combination of NLR in the first trimester and Model 3; Model 2 is a combination of PLR in the first trimester and Model 3; Model 3 is a combination of maternal gestational obesity, advanced maternal age and nulliparity. ROC: Receiver operating characteristic; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio.
Logistic回归分析显示，模型1中孕早期NLR的OR值为0.92（95%CI，0.77～1.09；P=0.33），模型2中孕早期PLR的OR值为1.00（95%CI，0.99～1.01；P=0.35）。ROC分析显示，未经联合NLR或PLR前，模型3的AUC为0.84（95%CI，0.79～0.90）。联合NLR的模型1的AUC为0.85（95%CI，0.79～0.90），联合PLR的模型2的AUC为0.85（95%CI，0.80～0.90）（图1B）。
3. 讨论
本研究发现，子痫前期组和正常妊娠组NLR均显著高于正常非妊娠组，支持妊娠期炎症存在。子痫前期组和正常妊娠组孕中、晚期PLR明显低于正常非妊娠组，可能与妊娠期间的生理性血液稀释和血小板减少有关[14]。本研究中，正常妊娠女性NLR呈现先升后降的趋势，与KLEMENT等[15]的结果相同；而正常妊娠女性和子痫前期患者的NLR变化趋势与BULBUL等[16]的结果不同，可能与采血时期、研究对象不完全相同有关，BULBUL等的采血时期分别为孕10～12周、孕22～24周和孕28～30周，仅纳入重度子痫前期。此外，本研究还发现正常妊娠女性和子痫前期患者的PLR均随妊娠进展呈持续下降的趋势，与BULBUL等的结果相同。
本研究发现，无论正常妊娠还是子痫前期，高龄和非高龄亚组之间NLR和PLR的差异无统计学意义；研究发现，孕期NLR和PLR与孕妇年龄相关度低（r<0.2）[15]。有研究认为，肥胖可致亚临床炎症[17]，肥胖患者NLR和PLR均高于正常BMI人群、NLR和PLR与BMI正相关[18-19]。本研究发现，子痫前期和正常妊娠的NLR和PLR均不受孕前BMI影响。
近年来，有学者关注NLR和PLR对子痫前期的预测价值，但结果却不统一。OĞLAK等[10]发现，子痫前期组孕早期NLR 和PLR均显著高于正常妊娠组，孕早期NLR 和PLR对子痫前期具有预测价值。LIAO等[20]发现，子痫前期组孕早期NLR 和PLR均显著高于正常妊娠组，但其预测子痫前期的价值有限。本研究中子痫前期组和正常妊娠组间孕早期NLR和PLR的差异均无统计学意义，提示两者对子痫前期的预测价值较低。鉴于孕前肥胖、高龄和初产因素是子痫前期的危险因素[21]，本研究分析显示联合高龄、孕前肥胖和初产因素对子痫前期有较好的预测价值；进一步联合孕早期NLR和PLR与高龄、孕前肥胖和初产因素建立新的子痫前期预测模型发现，联合后的AUC较联合前并无显著改善。
本研究的不足之处：首先，本研究是单中心回顾性研究，样本代表性有限，且回顾性研究的预测价值有限。其次，样本量较小，尤其子痫前期组。最后，NLR和PLR是孕早、中、晚期血细胞计数的计算结果，每个孕期都是相对较长的时期；进一步缩短期限，结果可能更有价值。
综上，本研究发现，NLR和PLR不是子痫前期的独立影响因素，不能提高对子痫前期的预测价值。
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利益冲突 所有作者均声明不存在利益冲突
Funding Statement
国家自然科学基金（No. 81571465，No. 81871175）和四川省科技厅科技计划项目（重点研发项目）（No. 2021YFS0208）资助
Contributor Information
红彪 喻 (Hong-biao YU), Email: yuhbyuhb@qq.com.
容 周 (Rong ZHOU), Email: zhourong_hx@scu.edu.cn.
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