Abstract
目的
探索自然受孕、单胎妊娠、阴道自然分娩妇女围受孕期服用叶酸或含叶酸的多种微量营养素补充剂与早产发生风险的关联。
方法
基于北京市通州区妇幼保健院孕期保健系统和医院信息系统开展回顾性队列研究，收集2015年1月至2018年12月自然受孕、单胎妊娠、在北京市通州区妇幼保健院进行产前保健并阴道自然分娩的16 332名孕产妇的信息，将妇女服用营养补充剂的开始时间与频率相结合形成依从性得分。采用Logistic回归模型分析妇女围受孕期是否服用单纯叶酸片(folic acid，FA)或含叶酸的多种微量营养素补充剂(multiple-micronutrients containing folic acid，MMFA)、服用方式、服用依从性得分与早产率的关系。
结果
研究人群的早产率(孕周 < 37周)为3.8%，平均孕龄为(38.98±1.37)周，其中，有6 174(37.8%)名妇女在围受孕期服用了FA，8 646(52.9%)名服用了MMFA，1 512(9.3%)名未服用任何营养补充剂。与未服用营养补充剂的妇女相比，服用FA或MMFA与早产的关联没有统计学意义[调整后的比值比(adjusted odds ratio，aOR)=1.01，95%CI：0.74~1.37]，服用营养补充剂的种类、开始服用时间及频率与早产的关联也未见统计学意义；同样，也未发现围受孕期服用营养补充剂的依从性得分与早产的关联有统计学意义。
结论
尚未发现自然受孕、单胎妊娠、阴道自然分娩的妇女在围受孕期服用FA或MMFA与早产之间的关联，未来需要开展更多的多中心、大规模前瞻性队列研究或随机对照研究来论证妇女围受孕期服用FA或MMFA与早产之间的关联。
Keywords: 叶酸, 多种微量营养素, 早产, 围受孕期
Abstract
Objective
To explore the association between periconceptional supplementation of folic acid or multiple-micronutrients containing folic acid(MMFA) and risk of preterm delivery in women with natural conception, singleton pregnancy and vaginal delivery.
Methods
A retrospective cohort study was performed based on the prenatal health care system and hospital information system of Tongzhou Maternal and Child Health Hospital of Beijing and the women who had their prenatal care in the hospital from January 2015 to December 2018 were included. The information of 16 332 women who conceived naturally, had a singleton pregnancy, and delivered vaginally was collected. Compliance scores were constructed based on the time of initiation and the frequency of taking nutritional supplements. The association between maternal periconceptional micronutrient supplementation, including pure folic acid (FA) pills or MMFA and the rate of preterm delivery was evaluated using Logistic regression models.
Results
The preterm delivery rate (gestational week < 37 weeks) of the study population was 3.8%, and the mean (standard deviation) of gestational age was (38.98±1.37) weeks. A total of 6 174 (37.8%) women took FA during the periconceptional period, 8 646 (52.9%) women took MMFA, and 1 512 (9.3%) women did not take any nutritional supplements. The association between periconceptional supplementation of FA or MMFA and risk of preterm delivery in women was not statistically significant [adjusted odds ratio (aOR)=1.01, 95%CI: 0.74-1.37]. The associations with preterm birth were not statistically significant in further analysis by the type of nutritional supplements, time of initiation, and the frequency of supplementation. In addition, the association between the compliance score of taking supplements and the rate of preterm delivery was not statistically significant, either.
Conclusion
This study did not find an association between the risk of preterm delivery and the use of FA or MMFA during the periconcep-tional period in women with natural conception, singleton pregnancy, and vaginal delivery. In the future, multicenter studies with large-scale prospective cohort or population-based randomized controlled trials are warranted to confirm the association between taking FA or MMFA during the periconceptional period and preterm delivery among women.
Keywords: Folic acid, Multiple-micronutrient, Premature birth, Periconceptional period
早产，即胎儿在37周之前出生，是常见的妊娠并发症，发生率为5%~18%。近几十年来，多数国家或地区的早产率呈上升趋势，2010年全球有1 500万早产儿出生[1]。我国的新生儿早产率处于中等水平，但最新研究显示，2012—2018年呈上升趋势[2]。2010年中国有117.23万早产儿，早产总例数位居世界第二[1]。早产是围产儿[3]及5岁以下儿童死亡的主要原因[4]，与足月儿相比，早产儿发生脑瘫、认知障碍和视力异常等神经系统发育异常的风险均更高，另外，早产还影响成年后的身心健康[5]。因此，降低早产率对提高人群健康状况、促进个人健康和长期发展具有重要意义。
叶酸，也称维生素B9，是一种水溶性维生素，其生理作用是参与体内嘌呤和胸苷酸生物合成、氨基酸代谢、氧化反应等多种单碳转移反应[6]。在妊娠期，胎儿、胎盘的生长和母体的生理状态变化对叶酸的需求均增加，如果这种增加需求无法满足，则会对母体和胎儿造成不利影响[7]。适时服用叶酸营养补充剂可以缓解叶酸缺乏，降低健康损害[8]。常用的叶酸营养补充剂有单纯叶酸片(folic acid, FA)和含叶酸的复方营养补充剂(multiple-micronutrient containing folic acid，MMFA)。复方营养补充剂中除了含有叶酸外，还含有维生素A、B、C、D、E以及铁、钙、镁、锌等矿物质。
虽然已有研究证明母亲围受孕期补充叶酸可以有效预防胎儿神经管缺陷，还有可能减少先天性心脏病[9]、低出生体质量和小于胎龄儿等不良妊娠结局[10-12]，但围受孕期补充叶酸与早产之间的关联尚缺乏明确结论[13]。在高收入国家的研究中没有发现关联[14]，而对中、低收入国家的研究则认为围受孕期补充营养素可以降低早产率[15]。我国实施了人群增补叶酸预防神经管缺陷的公共卫生项目之后，大约有90%的北京妇女在围受孕期服用叶酸或含叶酸的营养补充剂[16]，为开展围受孕期补充营养补充剂与早产的关系提供了重要基础数据。本研究以2015—2018年在北京市通州区妇幼保健院进行孕期保健并分娩妇女的孕期保健和医疗记录信息为基础，探索妇女围受孕期补充FA或MMFA与早产的关联，为孕期保健指导和早产预防提供参考。
1. 资料与方法
1.1. 资料来源
研究数据来源于北京市通州区的孕期保健系统和通州区妇幼保健院的医院信息系统，主要指标包括：妇女的一般人口学特征、妇产科特征、疾病史和服用微量营养补充剂信息(是否服用、服用种类、服用时间与频率)。本研究已获得北京大学生物医学伦理委员会批准(IRB00001052-18010)。
1.2. 研究对象
研究纳入2015年1月1日至2018年12月31日孕早期在北京市通州区孕期保健系统注册，并在通州区妇幼保健院进行规律孕检且阴道自然分娩的妇女共16 504人。由于非阴道自然产的新生儿，其母亲可能存在影响其孕周的社会学原因，而系统中并未对此进行全面记录，因此未将非阴道自然产的妇女纳入本研究。在此基础上，根据研究目的，剔除了84名辅助生殖技术受孕，50名具有死胎、死产不良妊娠结局，19名双胎妊娠，14名围受孕期服用营养补充剂种类缺失，5名孕周缺失或者小于28周的妇女信息后，最终本研究共纳入16 332 (98.8%)名妇女，研究对象的筛选流程见图 1。
图 1.
研究对象的筛选流程
Flowchart of participants selection
1.3. 指标定义
围受孕期是指本次妊娠的末次月经前12周至末次月经后12周的时期[17]。
叶酸服用信息包括是否服用营养补充剂(FA或MMFA)、服用补充剂种类、服用是否规律和开始服用时间，其中，FA的叶酸含量为400 μg/片，MMFA的叶酸含量有800 μg/片和400 μg/片两种。孕前、孕后是指在本次妊娠末次月经前和月经后。规律(高频)服用是指10天内服用8天及以上，不规律(低频)服用是指10天内服用营养补充剂的天数小于8天。
孕龄=分娩日期-末次月经日期。早产定义为胎儿在满37周之前分娩，足月为在37~41 +6周内分娩；足月产进一步分为早期足月产(37~38 +6周)、完全足月产(39~40+6周)、晚期足月产(41~41 +6周)[18]。
体重指数(body mass index，BMI)的计算公式为体质量(kg)/身高(m)2。孕前BMI分类参照中国肥胖工作组制定的标准：18.5~23.9 kg/m2为正常， < 18.5 kg/m2为偏瘦，24.0~27.9 kg/m2为超重，≥28.0 kg/m2为肥胖[19]。
1.4. 统计学分析
定性指标使用频数和百分比进行描述，定量指标使用平均值±标准差、最小值、最大值、中位数、P25和P75来描述。使用卡方检验比较三组(FA、MMFA、未服用)妇女间定性指标的差异，使用方差分析(正态资料)或秩和检验(非正态资料)对定量指标进行比较分析。
以完全足月为参照组，以早产为对比组，以妇女在孕期是否服用叶酸、服用种类、开始服用时间及服用频率为自变量，分别进行单因素和多因素Logistic回归模型计算调整前后的比值比(odds ratio，OR)及95%置信区间(confidence interval，CI)，以探索妇女围受孕期服用FA或MMFA与早产之间的关系。将组间比较P < 0.05及既往文献报道可能为混杂因素的基线特征指标纳入多因素Logistic回归模型中，最终放入模型调整的混杂因素包括：年龄、民族、文化程度、孕前BMI、产次、职业、户籍地、妊娠期糖尿病、妊娠期高血压以及分娩年份指标。因纳入模型的协变量中最大缺失比例小于3%，所以分析中未对缺失值进行处理，直接以原始采集数据进行分析。
为探索妇女围受孕期服用FA和MMFA的依从性与早产的关系，将FA和MMFA的服用时间与服用频率相结合形成依从性得分。依从性分为不服用、孕后开始不规律服用、孕后开始规律服用、孕前开始不规律服用和孕前开始规律服用5个等级。考虑到孕后开始规律服用FA或MMFA的人数过少(分别为31人和74人)，故将这两组从对应分析人群中剔除，最终FA和MMFA的依从性得分为4个等级：未服用(0分)、孕后开始不规律服用(1分)、孕前开始不规律服用(2分)、孕前开始规律服用(3分)。
使用SAS 9.4软件进行统计分析，统计检验显著性水准为双侧P < 0.05。
2. 结果
在16 332名妇女中，有6 174(37.8%)名在围受孕期服用了FA，8 646(52.9%)名服用了MMFA，1 512(9.3%)例未服用任何营养补充剂，不同叶酸服用方式妇女的基本特征见表 1。未服用任何营养补充剂、服用FA和MMFA三组妇女之间年龄分布、受教育水平、职业和初产妇比例及妊娠期糖尿病患病率的差异有统计学意义。
表 1.
研究对象的基本特征
General characteristics of the participants in the study
| Characteristics | Total, n (%) (n=16 332) |
FA, n (%) (n=6 174) |
MMFA, n (%) (n=8 646) |
No use, n (%) (n=1 512) |
χ 2 | P |
| BMI, body mass index; FA, folic acid; MMFA, multiple-micronutrients containing folic acid. | ||||||
| Ethnic | 1.983 | 0.371 | ||||
| Han | 15 403 (94.3) | 5 820 (94.3) | 8 145 (94.2) | 1 438 (95.1) | ||
| Others | 929 (5.7) | 354 (5.7) | 501 (5.8) | 74 (4.9) | ||
| Maternal age/years | 58.013 | < 0.001 | ||||
| 16- | 2 245 (13.7) | 844 (13.7) | 1 106 (12.8) | 295 (19.5) | ||
| 25- | 8 262 (50.6) | 3 157 (51.1) | 4 438 (51.3) | 667 (44.1) | ||
| 30- | 4 665 (28.6) | 1 742 (28.2) | 2 492 (28.8) | 431 (28.5) | ||
| 35-48 | 1 160 (7.1) | 431 (7.0) | 610 (7.1) | 119 (7.9) | ||
| Education level | 381.451 | < 0.001 | ||||
| Missing | 132 (0.8) | 42 (0.7) | 49 (0.6) | 41 (2.7) | ||
| Middle school or lower | 1 618 (10.0) | 678 (11.1) | 651 (7.6) | 289 (19.6) | ||
| High school or secondary technical school | 3 152 (19.5) | 1 212 (19.8) | 1 526 (17.8) | 414 (28.1) | ||
| College | 5 095 (31.5) | 1 929 (31.5) | 2 760 (32.1) | 406 (27.6) | ||
| University or above | 6 335 (39.1) | 2 313 (37.7) | 3 660 (42.6) | 362 (24.6) | ||
| Occupation | 221.993 | < 0.001 | ||||
| Missing | 368 (2.3) | 125 (2.0) | 140 (1.6) | 103 (6.8) | ||
| Government agency | 1 513 (9.5) | 536 (8.9) | 799 (9.4) | 178 (12.6) | ||
| Professional technicians | 3 405 (21.3) | 1 327 (21.9) | 1 903 (22.4) | 175 (12.4) | ||
| Office clerk or related personnel | 2 519 (15.8) | 857 (14.2) | 1 500 (17.6) | 162 (11.5) | ||
| Business/services | 3 077 (19.3) | 1 194 (19.7) | 1 653 (19.4) | 230 (16.3) | ||
| Unemployment | 2 581 (16.2) | 1 018 (16.8) | 1 258 (14.8) | 305 (21.6) | ||
| Others | 2 869 (18.0) | 1 117 (18.5) | 1 393 (16.4) | 359 (25.5) | ||
| Parents household registration types | 30.894 | < 0.001 | ||||
| Both of parents were none local | 6 802 (41.6) | 2 584 (41.9) | 3 576 (41.4) | 642 (42.5) | ||
| The mother registered locally | 6 383 (39.1) | 2 287 (37.0) | 3 515 (40.7) | 581 (38.4) | ||
| Only the father registered locally | 3 147 (19.3) | 1 303 (21.1) | 1 555 (18.0) | 289 (19.1) | ||
| Pre-pregnancy BMI | 8.330 | 0.215 | ||||
| Missing | 21 (0.1) | 6 (0.1) | 11 (0.1) | 4 (0.3) | ||
| Underweight | 2 251 (13.8) | 826 (13.4) | 1 227 (14.2) | 198 (13.1) | ||
| Normal | 10 737 (65.8) | 4 078 (66.1) | 5 689 (65.9) | 970 (64.3) | ||
| Overweight | 2 627 (16.1) | 988 (16.0) | 1 368 (15.8) | 271 (18.0) | ||
| Obesity | 696 (4.3) | 276 (4.5) | 351 (4.1) | 69 (4.6) | ||
| Parity | 133.442 | < 0.001 | ||||
| Missing | 460 (2.8) | 205 (3.3) | 245 (2.8) | 10 (0.7) | ||
| Nulliparity | 9 026 (56.9) | 3 536 (59.2) | 4 844 (57.7) | 646 (43.0) | ||
| Multiparity | 6 846 (43.1) | 2 433 (40.8) | 3 557 (42.3) | 856 (57.0) | ||
| Pre-pregnant diabetes | 2.242 | 0.326 | ||||
| No | 16 219 (99.3) | 6 128 (99.3) | 8 593 (99.4) | 1 498 (99.1) | ||
| Yes | 113 (0.7) | 46 (0.7) | 53 (0.6) | 14 (0.9) | ||
| Gestational diabetes | 15.378 | 0.001 | ||||
| No | 12 706 (77.8) | 4 793 (77.6) | 6 677 (77.2) | 1 236 (81.7) | ||
| Yes | 3 626 (22.2) | 1 381 (22.4) | 1 969 (22.8) | 276 (18.3) | ||
| Gestational hypertension | 1.911 | 0.385 | ||||
| No | 15 648 (95.8) | 5 899 (95.5) | 8 295 (95.9) | 1 454 (96.2) | ||
| Yes | 684 (4.2) | 275 (4.5) | 351 (4.1) | 58 (3.8) | ||
| Liver disease | 0.872 | 0.647 | ||||
| No | 16 045 (98.2) | 6 069 (98.3) | 8 495 (98.3) | 1 481 (97.9) | ||
| Yes | 287 (1.8) | 105 (1.7) | 151 (1.7) | 31 (2.1) | ||
| Thyroid disease | 0.968 | 0.617 | ||||
| No | 15 593 (95.5) | 5 882 (95.3) | 8 265 (95.6) | 1 446 (95.6) | ||
| Yes | 739 (4.5) | 292 (4.7) | 381 (4.4) | 66 (4.4) | ||
| Delivery year | 231.248 | < 0.001 | ||||
| 2015 | 3 016 (18.5) | 1 149 (18.6) | 1 436 (16.6) | 431 (28.5) | ||
| 2016 | 5 054 (30.9) | 2 166 (35.1) | 2 554 (29.5) | 334 (22.1) | ||
| 2017 | 4 506 (27.6) | 1 640 (26.6) | 2 470 (28.6) | 396 (26.2) | ||
| 2018 | 3 756 (23.0) | 1 219 (19.7) | 2 186 (25.3) | 351 (23.2) | ||
本研究人群中，早产的总发生率为3.8%(618/16 332名)，服用FA、MMFA和未服用的妇女早产率分别为4.2%(258/6 174名)、3.5%(305/8 646名)、3.6%(55/1 512名)。研究人群的平均孕龄为(38.98±1.37)周，服用和未服用营养补充剂的妇女平均孕龄为(38.97±1.37)周和(38.99±1.40)周(P=0.743)，服用FA和MMFA的妇女平均孕龄为(38.96±1.39)周和(38.98±1.35)周(P=0.348)。服用FA的妇女在孕前开始服用营养补充剂和规律服用的比例更高，见表 2。
表 2.
围受孕期服用营养补充剂的配方、开始时间和频率与孕龄的关系
Relationship between the formula, time of initiation, frequency of taking nutritional supplements in the periconceptional period and gestational age
| Use of nutritional supplements | n (%) | Gestational age/weeks | ||||||
| x±s | P 10 | P 25 | P 50 | P 75 | P 90 | P value | ||
| a, t test. P10-P90, 10th-90th quantile. FA, folic acid; MMFA, multiple-micronutrients containing folic acid. | ||||||||
| Total | 16 332 (100.0) | 38.98±1.37 | 37 | 38 | 39 | 40 | 40 | |
| Nutritional supplements | 0.743a | |||||||
| No | 1 512 (9.3) | 38.99±1.40 | 38 | 38 | 39 | 40 | 40 | |
| Yes | 14 820 (90.7) | 38.97±1.37 | 37 | 38 | 39 | 40 | 40 | |
| Supplements formula | 0.348a | |||||||
| FA | 6 174 (41.7) | 38.96±1.39 | 37 | 38 | 39 | 40 | 40 | |
| MMFA | 8 646 (58.3) | 38.98±1.35 | 37 | 38 | 39 | 40 | 40 | |
| FA | ||||||||
| Timing of supplementation initiation | 0.755a | |||||||
| Before the conception | 3 614 (58.5) | 38.96±1.36 | 37 | 38 | 39 | 40 | 40 | |
| After the conception | 2 560 (41.5) | 38.97±1.44 | 38 | 38 | 39 | 40 | 40 | |
| Frequercy (in 10 d) | 0.981a | |||||||
| Irregular (< 8 d) | 2 921 (47.3) | 38.96±1.44 | 38 | 38 | 39 | 40 | 40 | |
| Regular (≥8 d) | 3 253 (52.7) | 38.96±1.35 | 37 | 38 | 39 | 40 | 40 | |
| MMFA | ||||||||
| Timing of supplementation initiation | 0.012a | |||||||
| Before the conception | 3 395 (39.3) | 38.94±1.37 | 37 | 38 | 39 | 40 | 40 | |
| After the conception | 5 251 (60.7) | 39.01±1.33 | 38 | 38 | 39 | 40 | 40 | |
| Frequercy (in 10 d) | 0.072a | |||||||
| Irregular (< 8 d) | 5 597 (64.8) | 39.00±1.36 | 38 | 38 | 39 | 40 | 40 | |
| Regular (≥8 d) | 3 047 (35.2) | 38.95±1.33 | 37 | 38 | 39 | 40 | 40 | |
调整混杂因素后，与未服用营养补充剂的妇女相比，服用FA和MMFA与早产的关联无统计学意义[调整后的比值比(adjusted odds ratio，aOR)=1.01，95%CI：0.74~1.37]。进一步按照营养补充剂种类、服用时间及频率进行分层，也未见服用营养补充剂与早产的关联有统计学意义(CI均包含1，表 3)；同样，也未发现围受孕期服用营养补充剂依从性不同的妇女间早产率差异有统计学意义(CI均包含1，表 4)。
表 3.
围受孕期服用营养补充剂的配方、开始时间和频率与早产的关系
Association of nutritional supplement formula, time of initiation and frequency with preterm delivery
| Use of nutritional supplements | Preterm delivery | ||
| % (n/N) | cOR (95%CI) | aOR (95%CI)* | |
| * The adjusted confounders include maternal age, ethnicity, education levels, occupation, pre-pregnant body mass index, parity, gestational diabetes, gestational hypertension, delivery year, and parental household registration. cOR, crude odds ratio; aOR, adjusted odds ratio; FA, folic acid; MMFA, multiple-micronutrients containing folic acid. N, total number. | |||
| Nutritional supplements | |||
| No | 5.58% (55/986) | 1 | 1 |
| Yes | 5.75% (563/9 785) | 1.03 (0.78-1.37) | 1.01 (0.74-1.37) |
| Supplements formula | |||
| FA | 6.34% (258/4 070) | 1 | 1 |
| MMFA | 5.34% (305/5 715) | 0.83 (0.70-0.99) | 0.85 (0.71-1.02) |
| FA | |||
| Timing of supplementation initiation | |||
| Before the conception | 6.15% (145/2 359) | 0.93 (0.72-1.19) | 0.90 (0.68-1.18) |
| After the conception | 6.60% (113/1 711) | 1 | 1 |
| Frequency (in 10 d) | |||
| Irregular (< 8 d) | 6.54% (127/1 942) | 1 | 1 |
| Regular (≥8 d) | 6.16% (131/2 128) | 0.94 (0.73-1.21) | 0.93 (0.71-1.22) |
| MMFA | |||
| Timing of supplementation initiation | |||
| Before the conception | 5.50% (123/2 237) | 1.05 (0.83-1.33) | 0.95 (0.74-1.22) |
| After the conception | 5.23% (182/3 478) | 1 | 1 |
| Frequency (in 10 d) | |||
| Irregular (< 8 d) | 5.38% (199/3 697) | 1 | 1 |
| Regular (≥8 d) | 5.25% (106/2 018) | 0.97 (0.76-1.24) | 0.87 (0.67-1.12) |
表 4.
围受孕期服用营养补充剂的依从性得分与早产的关系
Association between compliance score of taking nutritional supplements in the peri-conceptional period and preterm delivery
| Compliance score | Preterm delivery | ||
| % (n/N) | cOR (95%CI) | aOR (95%CI)* | |
| * The confounders include maternal age, ethnicity, education levels, occupation, pre-pregnant body mass index, parity, gestational diabetes, gestational hypertension, delivery year, and parental household registration. Abbreviations as in Table 3. | |||
| FA | |||
| 0 | 5.58% (55/986) | 1 | 1 |
| 1 | 6.62% (112/1 691) | 1.20 (0.86-1.67) | 1.19 (0.84-1.70) |
| 2 | 5.98% (15/251) | 1.08 (0.60-1.94) | 0.99 (0.53-1.85) |
| 3 | 6.17% (130/2 108) | 1.11 (0.80-1.54) | 1.08 (0.76-1.54) |
| MMFA | |||
| 0 | 5.58% (55/986) | 1 | 1 |
| 1 | 5.23% (179/3 424) | 0.93 (0.68-1.27) | 0.96 (0.69-1.34) |
| 2 | 7.33% (20/273) | 1.34 (0.79-2.27) | 1.36 (0.78-2.36) |
| 3 | 5.24% (103/1 964) | 0.94 (0.67-1.31) | 0.86 (0.59-1.24) |
3. 讨论
全世界184个国家中，早产发生率的范围为5%~18%[1]。根据中国国家孕产妇不良事件监测系统(China’ s National Maternal Near Miss Surveillance System，NMNMSS)对2012—2018年964万例孕产数据的统计，中国的早产率为6. 1%，其中单胎妊娠的加权早产率为5.4%[2]。本研究人群的早产率为3.8%，低于WHO的报道以及NMNMSS的监测结果，这可能与本研究人群来自经济发达的大城市，医疗条件较好，且本研究仅纳入了自然受孕、单胎妊娠和自然分娩的妇女有关。
本研究未发现围受孕期未服用营养补充剂与服用FA或MMFA的妇女之间早产率差异有统计学意义；在服用FA和MMFA的妇女中，进一步按照服用补充剂种类、开始服用时间与服用频率进行分层和形成依从性得分进行剂量效应分析，也未见服用FA或MMFA与早产之间的关联有统计学意义。上述结果与2016年发表的一项包含5项随机对照试验研究的系统评价和荟萃分析[20]，以及另外两个队列研究[21-22]的结果一致。但是，20世纪90年代在我国南方两省(浙江和江苏)农村地区进行的一项大型队列研究结果显示，围受孕期服用FA的妇女整体早产风险降低14%[23]。本研究结果与之存在差异可能主要是由于本研究的数据收集时间为2015—2018年，较该研究晚了大约20年，这20年也是中国经济发展较快的时期，随着经济条件的改善，人群整体营养状况随之提高，且妇女的健康保健意识也有较大提升，在备孕期和怀孕后更加注重食物的多样性和营养的均衡，故围受孕期服用FA或MMFA对早产率的影响可能会较之前减弱。另一项在中国西南地区进行的回顾性队列研究发现，与未服用FA的女性相比，在末次月经前开始服用FA的妇女早产风险降低，但在末次月经后开始服用FA并未降低早产的风险[24]。本研究中，不管妇女围受孕期开始服用FA的时间是在孕前还是孕后，均没有发现其与早产之前的关联有统计学意义，这可能与本研究人群的文化程度较高，且所在地区经济较为发达，因而妇女本身的健康素养较高，更加注重围受孕期营养有关。
本研究具有以下几个方面的优势，首先，研究样本量较大，有足够的把握度按照服用营养补充剂的种类、开始服用时间及服用频率分层后对服用FA或MMFA与早产间的关联进行评估；其次，本研究中有关营养补充剂服用情况的信息是妇女孕早期进行孕期保健系统中注册时收集的，回忆偏倚较小；第三，所有研究对象的分娩孕周信息均来自医院的信息系统，由产科医生在妇女住院分娩时记录，准确性较高；第四，本研究排除了非自然受孕、多胎和非自然分娩的妇女，且在数据分析过程中除了调整一般人口学特征外，还调整了妊娠期糖尿病、妊娠期高血压等妊娠期合并症，以及其他一些可能影响早产率的因素，研究结果的可靠性较好。
本研究也存在一些不足，首先，研究对象仅来自北京市通州区，其文化程度、年龄等特征与国内其他地区孕产妇的平均水平存在差异，研究结果只能外推至经济和人群类似的地区；其次，本研究未采集妇女通过膳食摄入叶酸和其他营养素的信息，难以排除其对研究结果的干扰；第三，本研究没有收集孕妇的血浆叶酸浓度信息，只能通过服用开始时间、服用的频率高低及依从性得分来估计服用叶酸的剂量，进行剂量效应分析。但是，本研究收集了孕早期血浆同型半胱氨酸(homocysteine，Hcy)数据，根据既往研究结果，叶酸缺乏会导致血浆Hcy浓度升高，所以血浆Hcy水平可反映血浆中叶酸水平[25]。本研究中，围受孕期服用补充剂的妇女孕早期Hcy水平明显低于不服用者，服用MMFA的妇女(其中60%服用的补充剂含800 μg FA)的Hcy水平明显低于仅服用FA者，且开始服用的时间越早、服用频率越高，Hcy水平越低。无论是围受孕期服用FA的妇女还是服用MMFA的妇女，服用营养补充剂的依从性得分越高，其血浆Hcy水平越低。上述结果均可证明本研究中妇女围受孕期服用营养补充剂信息的准确性。
总之，本研究尚未发现自然受孕、单胎妊娠、阴道自然分娩的妇女围受孕期服用FA或MMFA与早产之间存在关联。未来还需要开展多中心、大规模前瞻性队列或随机干预试验研究，明确孕期妇女服用FA或MMFA营养补充剂与早产之间的关联，以更好地为孕期保健及预防早产提供参考依据。
Funding Statement
首都卫生发展科研专项(2020-1-5112)和国家社科基金重大项目(21&ZD187)
Supported by the Capital Health Research and Development of Special (2020-1-5112) and the National Social Science Fund of China (21&ZD187)
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