孕妇稳定补充叶酸后的血清叶酸水平及其影响因素分析

doi:10.3877/cma.j.issn.1673-5250.2022.05.009

目的

探讨稳定补充叶酸后，孕妇血清叶酸水平及其影响因素。

方法

选择2019年8月至2020年12月，于复旦大学妇产科医院进行产前检查，并且在正常饮食情况下稳定补充叶酸(400 μg/d×60 d)后的718例孕龄为12~24孕周孕妇为研究对象。根据补充叶酸后的血清叶酸水平，将其分为4组：A组(n＝23，血清叶酸水平<7 ng/mL)，B组(n＝170，血清叶酸水平为≥7~14 ng/mL)，C组(n＝217，血清叶酸水平为≥14~18 ng/mL)，D组(n＝308，血清叶酸水平为≥18~20 ng/mL)。采用χ²检验及秩和检验，对4组孕妇一般临床资料及血清维生素B12水平、同型半胱氨酸(Hcy)浓度进行统计学比较(单因素分析)。对孕妇稳定补充叶酸后上述4个血清叶酸水平的影响因素，采用无序多分类logistic回归法进行分析。本研究遵循的程序符合2013年修订的《世界医学协会赫尔辛基宣言》。获取所有受试者的知情同意，并与其签署临床研究知情同意书。

结果

①单因素分析结集显示：4组孕妇血清Hcy浓度、维生素B12水平，孕龄≥12~19孕周与≥19~25孕周构成比比较，差异均有统计学意义(均为P<0.001)。②相对于血清叶酸水平为<7 ng/mL：孕妇血清Hcy浓度每增加1 μmol/L，血清叶酸水平为≥7~14 ng/mL、≥14~18 ng/mL、≥18~20 ng/mL的可能性分别降低到原来的0.731倍(OR＝0.731)、0.353倍(OR＝0.353)、0.471倍(OR＝0.471)；孕妇血清维生素B12水平每增加1 pg/mL，血清叶酸水平为≥14~18 ng/mL的可能性增加到原来的1.004倍(OR＝1.004)。③相对于血清叶酸水平为≥7~14 ng/mL：孕妇血清Hcy浓度每增加1 μmol/L，血清叶酸水平为<7 ng/mL、≥14~18 ng/mL、≥18~20 ng/mL的可能性分别为增加到原来的1.369倍(OR＝1.369)、降低到原来的0.483倍(OR＝0.483)、降低到原来的0.644倍(OR＝0.644)；孕妇血清维生素B12水平每增加1 pg/mL，血清叶酸水平为≥14~18 ng/mL、≥18~20 ng/mL的可能性分别增加到原来的1.003倍(OR＝1.003)、1.003倍(OR＝1.003)；孕龄≥12~19孕周孕妇血清叶酸水平为≥18~20 ng/mL的可能性是孕龄≥19~25孕周孕妇的2.244倍(OR＝2.244)。④相对于血清叶酸水平为≥14~18 ng/mL：孕妇血清Hcy浓度每增加1 μmol/L，血清叶酸水平为<7 ng/mL、≥7~14 ng/mL、≥18~20 ng/mL的可能性均分别增加到原来的2.832倍(OR＝2.832)、2.069倍(OR＝2.069)、孕妇1.333倍(OR＝1.333)；孕妇血清维生素B12水平每增加1 pg/mL，血清叶酸水平为<7 ng/mL、≥7~14 ng/mL的可能性均降低到原来的0.996倍(OR＝0.996)、0.997倍(OR＝0.997)。

结论

血清Hcy浓度及维生素B12水平，以及孕龄，均对孕妇稳定补充叶酸后的血清叶酸水平有影响：血清Hcy浓度主要为负向影响，血清维生素B12水平主要为正向影响，孕龄仅对血清叶酸水平较高级别有影响。

关键词: 孕龄, 孕期叶酸补充, 叶酸, 维生素B12, 高半胱氨酸, 叶酸缺乏, 孕妇

Objective

To investigate the serum folic acid level and its influencing factors in pregnant women with periconceptional folic acid supplementation.

Methods

A total of 718 pregnant women with gestational age of 12 to 24 weeks were enrolled in this study from August 2019 to December 2020 at the Obstetrics and Gynecology Hospital of Fudan University. They underwent prenatal examination and stably intaked folic acid supplementation (400 μg/d×60 d) under normal diet. According to serum folic acid level after folic acid supplementation, they were divided into 4 groups: group A (n=23, serum folic acid level <7 ng/mL), group B (n=170, serum folic acid level was ≥7-14 ng/mL), group C (n=217, serum folic acid level was ≥14-18 ng/mL), and group D (n=308, serum folic acid level was ≥18-20 ng/mL). Chi-square test and rank sum test were used to compare general clinical data and serum vitamin B12 level, serum Homocysteine (Hcy) concentration among four groups (monofactor analysis). Multi-classification logistic regression analysis method was used to analyze the influencing factors of 4 levels of serum folic acid of pregnant women after periconceptional folic acid supplementation. The study was conducted in accordance with World Medical Association Declaration of Helsinki revised in 2013. All subjects informed consent and signed the informed consent forms for the clinical study.

Results

① Monofactor analysis results showed that there were significant differences among four groups in serum Hcy concentration, serum vitamin B12 level and gestational age (≥12-19 gestational weeks, ≥19-25 gestational weeks)(P<0.001). ② Serum folic acid level of <7 ng/mL was taken as reference: with increased serum Hcy concentration by 1 μmol/L in pregnant women, the possibility of serum folic acid levels of ≥7-14 ng/mL, ≥14-18 ng/mL and ≥18-20 ng/mL were decreased to 0.731, 0.353 and 0.471 times (OR=0.731, 0.353, 0.471), respectively. With increased serum vitamin B12 level by 1 pg/mL in pregnant women, the possibility of serum folic acid levels of ≥14-18 ng/mL was increased to 1.004 times (OR=1.004). ③ Serum folic acid level of ≥7-14 ng/mL was taken as reference: with increased serum Hcy concentration by 1 μmol/L in pregnant women, the possibility of serum folic acid level of <7 ng/mL, ≥14-18 ng/mL and ≥18-20 ng/mL were increased to 1.369 times (OR=1.369), decreased to 0.483 times (OR=0.483) and decreased to 0.644 times (OR=0.644), respectively. With increased serum vitamin B12 level by 1 pg/mL in pregnant women, the possibility of serum folic acid level of ≥14-18 ng/mL and ≥18-20 ng/mL increased to 1.003 times (OR=1.003) and 1.003 times (OR=1.003), respectively. The possibility of serum folic acid level of ≥18-20 ng/mL in pregnant women with gestation age at ≥12-19 weeks was 2.244 times that of pregnant women with gestation age at ≥19-25 weeks (OR=2.244). ④ Serum folic acid level of ≥14-18 ng/mL was taken as reference: with increased serum Hcy concentration by 1 μmol/L in pregnant women, the possibility of serum folic acid level of <7 ng/mL, ≥7-14 ng/mL and ≥18-20 ng/mL were increased to 2.832, 2.069 and 1.333 times (OR=2.832, 2.069, 1.333), respectively. With increased serum vitamin B12 level by 1 pg/mL in pregnant women, the possibility of serum folic acid level of <7 ng/mL and ≥7-14 ng/mL were decreased to 0.996 and 0.997 times (OR=0.996, 0.997).

Conclusions

Serum Hcy concentration and serum vitamin B12 level, as well as gestational age have significant effects on serum folic acid level of pregnant women with periconceptional folic acid supplementation: serum Hcy concentration is mainly negative and serum vitamin B12 level is mainly positive affected serum folic acid level. Gestational age only affects the higher serum folic acid level in pregnant women.

Key words: Gestational age, Periconceptional folic acid supplementation, Folic acid, Vitamin B12, Homocysteine, Folic acid deficiency, Pregnant women

表1 4组孕妇一般临床资料及血清维生素B12、Hcy水平比较

组别	例数	年龄[例数(%)]			孕龄[例数(%)]		血清维生素B12水平[pg/mL，M(Q₁，Q₃)]
组别	例数	≥20~30岁	≥30~40岁	≥40~45岁	≥12~19孕周	≥19~25孕周	血清维生素B12水平[pg/mL，M(Q₁，Q₃)]
A组	23	9(39.1)	14(60.9)	0(0)	19(82.6)	4(17.4)	311.0(222.0，499.0)
B组	170	60(35.3)	102(60.0)	8(4.7)	139(81.8)	31(18.2)	346.2(257.4，471.6)
C组	217	60(27.6)	152(70.0)	5(2.4)	192(88.5)	25(11.5)	489.0(400.0，610.0)
D组	308	85(27.6)	216(70.1)	7(2.3)	285(92.5)	23(7.5)	465.8(360.3，575.0)
统计量		χ²＝4.57			χ²＝-3.54		Z＝70.82
P值		0.102			<0.001		<0.001
组别	例数	双胎/多胎[例数(%)]	胎儿NT增厚[例数(%)]	21-三体筛查阳性[例数(%)]	18-三体筛查阳性[例数(%)]	不良孕产史≥2次[例数(%)]	血清Hcy浓度[μmol/L，M(Q₁，Q₃)]
A组	23	0(0)	0(0)	0(0)	0(0)	1(4.4)	9.0(7.0，10.8)
B组	170	10(5.9)	7(4.1)	3(1.8)	0(0)	9(5.3)	7.0(6.0，8.0)
C组	217	14(6.5)	18(8.3)	7(3.2)	2(0.9)	14(6.5)	5.0(5.0，7.0)
D组	308	17(5.5)	10(3.2)	11(3.2)	1(0.3)	23(7.5)	6.0(5.1，7.0)
统计量		χ²＝-0.14	χ²＝-0.66	χ²＝-1.04	χ²＝-0.27	χ²＝-1.01	Z＝122.91
P值		0.888	0.509	0.297	0.789	0.312	<0.001

表1 4组孕妇一般临床资料及血清维生素B12、Hcy水平比较

组别	例数	年龄[例数(%)]			孕龄[例数(%)]		血清维生素B12水平[pg/mL，M(Q₁，Q₃)]
组别	例数	≥20~30岁	≥30~40岁	≥40~45岁	≥12~19孕周	≥19~25孕周	血清维生素B12水平[pg/mL，M(Q₁，Q₃)]
A组	23	9(39.1)	14(60.9)	0(0)	19(82.6)	4(17.4)	311.0(222.0，499.0)
B组	170	60(35.3)	102(60.0)	8(4.7)	139(81.8)	31(18.2)	346.2(257.4，471.6)
C组	217	60(27.6)	152(70.0)	5(2.4)	192(88.5)	25(11.5)	489.0(400.0，610.0)
D组	308	85(27.6)	216(70.1)	7(2.3)	285(92.5)	23(7.5)	465.8(360.3，575.0)
统计量		χ²＝4.57			χ²＝-3.54		Z＝70.82
P值		0.102			<0.001		<0.001
组别	例数	双胎/多胎[例数(%)]	胎儿NT增厚[例数(%)]	21-三体筛查阳性[例数(%)]	18-三体筛查阳性[例数(%)]	不良孕产史≥2次[例数(%)]	血清Hcy浓度[μmol/L，M(Q₁，Q₃)]
A组	23	0(0)	0(0)	0(0)	0(0)	1(4.4)	9.0(7.0，10.8)
B组	170	10(5.9)	7(4.1)	3(1.8)	0(0)	9(5.3)	7.0(6.0，8.0)
C组	217	14(6.5)	18(8.3)	7(3.2)	2(0.9)	14(6.5)	5.0(5.0，7.0)
D组	308	17(5.5)	10(3.2)	11(3.2)	1(0.3)	23(7.5)	6.0(5.1，7.0)
统计量		χ²＝-0.14	χ²＝-0.66	χ²＝-1.04	χ²＝-0.27	χ²＝-1.01	Z＝122.91
P值		0.888	0.509	0.297	0.789	0.312	<0.001

表2 影响孕妇稳定补充叶酸后血清叶酸水平的无序多分类logistic回归分析参数估计结果(以血清叶酸水平<7 ng/mL为参考类别)

血清叶酸水平^a(ng/mL)	影响因素	B	SE	Wald值	ν	P值	OR值	OR值95%CI
≥7~14	截距	4.488	1.059	17.966	1	0.001	—	—
	血清Hcy浓度(μmol/L)	-0.314	0.088	12.743	1	0.001	0.731	0.615~0.868
	血清维生素B12水平(pg/mL)	0.001	0.002	0.057	1	0.812	1.000	0.997~1.004
	孕龄为≥12~19孕周	-0.052	0.635	0.007	1	0.935	0.949	0.273~3.298
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥14~18	截距	7.565	1.206	39.326	1	0.001	—	—
	血清Hcy浓度(μmol/L)	-1.041	0.119	76.935	1	0.001	0.353	0.280~0.446
	血清维生素B12水平(pg/mL)	0.004	0.002	5.514	1	0.019	1.004	1.001~1.007
	孕龄为≥12~19孕周	0.208	0.672	0.096	1	0.757	1.231	0.330~4.595
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥18~20	截距	6.092	1.162	27.483	1	0.001	—	—
	血清Hcy浓度(μmol/L)	-0.754	0.108	48.588	1	0.001	0.471	0.381~0.582
	血清维生素B12水平(pg/mL)	0.003	0.002	3.803	1	0.051	1.003	1.000~1.006
	孕龄为≥12~19孕周	0.756	0.662	1.304	1	0.253	2.130	0.582~7.801
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—

表2 影响孕妇稳定补充叶酸后血清叶酸水平的无序多分类logistic回归分析参数估计结果(以血清叶酸水平<7 ng/mL为参考类别)

血清叶酸水平^a(ng/mL)	影响因素	B	SE	Wald值	ν	P值	OR值	OR值95%CI
≥7~14	截距	4.488	1.059	17.966	1	0.001	—	—
	血清Hcy浓度(μmol/L)	-0.314	0.088	12.743	1	0.001	0.731	0.615~0.868
	血清维生素B12水平(pg/mL)	0.001	0.002	0.057	1	0.812	1.000	0.997~1.004
	孕龄为≥12~19孕周	-0.052	0.635	0.007	1	0.935	0.949	0.273~3.298
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥14~18	截距	7.565	1.206	39.326	1	0.001	—	—
	血清Hcy浓度(μmol/L)	-1.041	0.119	76.935	1	0.001	0.353	0.280~0.446
	血清维生素B12水平(pg/mL)	0.004	0.002	5.514	1	0.019	1.004	1.001~1.007
	孕龄为≥12~19孕周	0.208	0.672	0.096	1	0.757	1.231	0.330~4.595
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥18~20	截距	6.092	1.162	27.483	1	0.001	—	—
	血清Hcy浓度(μmol/L)	-0.754	0.108	48.588	1	0.001	0.471	0.381~0.582
	血清维生素B12水平(pg/mL)	0.003	0.002	3.803	1	0.051	1.003	1.000~1.006
	孕龄为≥12~19孕周	0.756	0.662	1.304	1	0.253	2.130	0.582~7.801
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—

表3 影响孕妇稳定补充叶酸后血清叶酸水平的无序多分类logistic回归分析参数估计结果(以血清叶酸水平≥7~14 ng/mL为参考类别)

血清叶酸水平^a(ng/mL)	影响因素	B	SE	Wald值	ν	P值	OR值	OR值95%CI
<7	截距	-4.488	1.059	17.966	1	0.001	—	—
	血清Hcy浓度(μmol/L)	0.314	0.088	12.743	1	0.001	1.369	1.152~1.626
	血清维生素B12水平(pg/mL)	0.001	0.002	0.057	1	0.812	1.000	0.996~1.003
	孕龄为≥12~19孕周	0.052	0.635	0.007	1	0.935	1.053	0.303~3.660
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥14~18	截距	3.076	0.710	18.770	1	0.001	—	—
	血清Hcy浓度(μmol/L)	-0.727	0.087	70.445	1	0.001	0.483	0.408~0.573
	血清维生素B12水平(pg/mL)	0.003	0.001	23.878	1	0.001	1.003	1.002~1.005
	孕龄为≥12~19孕周	0.260	0.330	0.622	1	0.430	1.297	0.679~2.477
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥18~20	截距	1.603	0.642	6.234	1	0.013	—	—
	血清Hcy浓度(μmol/L)	-0.440	0.072	36.860	1	0.001	0.644	0.559~0.742
	血清维生素B12水平(pg/mL)	0.003	0.001	17.501	1	0.001	1.003	1.001~1.004
	孕龄为≥12~19孕周	0.808	0.315	6.590	1	0.010	2.244	1.211~4.160
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—

表3 影响孕妇稳定补充叶酸后血清叶酸水平的无序多分类logistic回归分析参数估计结果(以血清叶酸水平≥7~14 ng/mL为参考类别)

血清叶酸水平^a(ng/mL)	影响因素	B	SE	Wald值	ν	P值	OR值	OR值95%CI
<7	截距	-4.488	1.059	17.966	1	0.001	—	—
	血清Hcy浓度(μmol/L)	0.314	0.088	12.743	1	0.001	1.369	1.152~1.626
	血清维生素B12水平(pg/mL)	0.001	0.002	0.057	1	0.812	1.000	0.996~1.003
	孕龄为≥12~19孕周	0.052	0.635	0.007	1	0.935	1.053	0.303~3.660
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥14~18	截距	3.076	0.710	18.770	1	0.001	—	—
	血清Hcy浓度(μmol/L)	-0.727	0.087	70.445	1	0.001	0.483	0.408~0.573
	血清维生素B12水平(pg/mL)	0.003	0.001	23.878	1	0.001	1.003	1.002~1.005
	孕龄为≥12~19孕周	0.260	0.330	0.622	1	0.430	1.297	0.679~2.477
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥18~20	截距	1.603	0.642	6.234	1	0.013	—	—
	血清Hcy浓度(μmol/L)	-0.440	0.072	36.860	1	0.001	0.644	0.559~0.742
	血清维生素B12水平(pg/mL)	0.003	0.001	17.501	1	0.001	1.003	1.001~1.004
	孕龄为≥12~19孕周	0.808	0.315	6.590	1	0.010	2.244	1.211~4.160
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—

表4 影响孕妇稳定补充叶酸后血清叶酸水平的无序多分类logistic回归分析参数估计结果(以血清叶酸水平≥14~18 ng/mL为参考类别)

血清叶酸水平^a(ng/mL)	影响因素	B	SE	Wald值	ν	P值	OR值	OR值95%CI
<7	截距	-7.565	1.206	39.326	1	0.001	—	—
	血清Hcy浓度(μmol/L)	1.041	0.119	76.935	1	0.001	2.832	2.244~3.574
	血清维生素B12水平(pg/mL)	-0.004	0.002	5.514	1	0.019	0.996	0.993~0.999
	孕龄为≥12~19孕周	-0.208	0.672	0.096	1	0.757	0.812	0.218~3.030
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥7~14	截距	-3.076	0.710	18.770	1	0.001	—	—
	血清Hcy浓度(μmol/L)	0.727	0.087	70.445	1	0.001	2.069	1.746~2.452
	血清维生素B12水平(pg/mL)	-0.003	0.001	23.878	1	0.001	0.997	0.995~0.998
	孕龄为≥12~19孕周	-0.260	0.330	0.622	1	0.430	0.771	0.404~1.472
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥18~20	截距	-1.473	0.576	6.536	1	0.011	—	—
	血清Hcy浓度(μmol/L)	0.287	0.070	16.783	1	0.001	1.333	1.162~1.529
	血清维生素B12水平(pg/mL)	-0.001	0.001	2.036	1	0.154	0.999	0.998~1.000
	孕龄为≥12~19孕周	0.548	0.310	3.135	1	0.077	1.730	0.943~3.174
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—

表4 影响孕妇稳定补充叶酸后血清叶酸水平的无序多分类logistic回归分析参数估计结果(以血清叶酸水平≥14~18 ng/mL为参考类别)

血清叶酸水平^a(ng/mL)	影响因素	B	SE	Wald值	ν	P值	OR值	OR值95%CI
<7	截距	-7.565	1.206	39.326	1	0.001	—	—
	血清Hcy浓度(μmol/L)	1.041	0.119	76.935	1	0.001	2.832	2.244~3.574
	血清维生素B12水平(pg/mL)	-0.004	0.002	5.514	1	0.019	0.996	0.993~0.999
	孕龄为≥12~19孕周	-0.208	0.672	0.096	1	0.757	0.812	0.218~3.030
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥7~14	截距	-3.076	0.710	18.770	1	0.001	—	—
	血清Hcy浓度(μmol/L)	0.727	0.087	70.445	1	0.001	2.069	1.746~2.452
	血清维生素B12水平(pg/mL)	-0.003	0.001	23.878	1	0.001	0.997	0.995~0.998
	孕龄为≥12~19孕周	-0.260	0.330	0.622	1	0.430	0.771	0.404~1.472
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—
≥18~20	截距	-1.473	0.576	6.536	1	0.011	—	—
	血清Hcy浓度(μmol/L)	0.287	0.070	16.783	1	0.001	1.333	1.162~1.529
	血清维生素B12水平(pg/mL)	-0.001	0.001	2.036	1	0.154	0.999	0.998~1.000
	孕龄为≥12~19孕周	0.548	0.310	3.135	1	0.077	1.730	0.943~3.174
	孕龄为≥19~25孕周	0^b	—	—	0	—	—	—

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Analysis of serum folic acid level and its influencing factors after stable folic acid supplementation in pregnant women

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Analysis of serum folic acid level and its influencing factors after stable folic acid supplementation in pregnant women