The interaction between no folic acid supplementation during early pregnancy and preeclampsia increased the risk of preterm birth

Yi-Jie Zhang; Hong Jiang; Chengqiu Lu; Yi Sun; Shudong Cui; Chao Chen

doi:10.15537/smj.2023.44.3.20220695

Article Figures & Data

Figures

Tables

Download figure
Open in new tab
Download powerpoint
Figure 1
- Flowchart showing the recruitment process for participants.

Tables

Figures

View popup

Table 1

- Demographic characteristics of the study participants.

Characteristics	Total n=2942	Preterm n=1471	Term n=1471	t/P
Maternal age^*	30.20±5.202	30.50±5.589	29.89±4.765	<0.001
<20	56 (1.9)	40 (2.7)	16 (1.1)	<0.001
20-34	2252 (76.5)	1075 (73.1)	1177 (80.0)
≥35	634 (21.6)	356 (24.2)	278 (18.9)
Parity
Unipara	1448 (49.2)	658 (44.7)	790 (53.7)	<0.001
Multipara	1494 (50.8)	813 (55.3)	681 (46.3)
Race
Han	2777 (94.4)	1373 (93.3)	1404 (95.4)	0.013
Others	165 (5.6)	98 (6.7)	67 (4.6)
Maternal Education
Middle school or below	787 (26.7)	467 (31.7)	320 (21.8)	<0.001
High school	688 (23.4)	377 (5.6)	311 (21.1)
University or above	1467 (49.9)	627 (42.6)	840 (57.1)
Residence during pregnancy
City	1482 (50.4)	650 (44.2)	832 (56.6)	<0.001
Small town	1062 (36.1)	568 (38.6)	494 (33.6)
Countryside	398 (13.5)	253 (17.2)	145 (9.8)
Family income monthly per person (yuan)
<2,000	224 (7.6)	141 (9.6)	83 (5.6)	<0.001
2,000-10,000	2115 (71.9)	1053 (71.6)	1062 (72.2)
>10,000	603 (20.5)	277 (18.8)	326 (22.2)

Values are presented as numbers and percentages (%).
↵* mean±standard deviation

View popup

Table 2

- Results arising from univariate analysis of the risk factors for PTB.

Characteristics	Total n=2942	Preterm n=1471	Term n=1471	P-value
Supplementation of FA in early pregnancy
No	1045 (35.5)	589 (40.0)	1456 (31.0)	<0.001
Full	1897 (64.5)	882 (60.0)	1015 (69.0)
Preeclampsia
No	2721 (92.5)	1272 (86.5)	21449 (98.5)	<0.001
Yes	221 (7.5)	199 (13.5)	122 (1.5)
Smoking in pregnancy
No	2758 (93.7)	1354 (92.0)	1404 (95.4)	<0.001
Yes	184 (6.3)	117 (8.0)	67 (4.6)
Previous preterm birth
No	2830 (96.2)	1377 (93.6)	1453 (98.8)	<0.001
Yes	112 (3.8)	94 (6.4)	18 (1.2)
Diabetes mellitus in pregnancy
No	2438 (82.9)	1176 (79.9)	1262 (85.8)	<0.001
Yes	504 (17.1)	295 (20.1)	209 (14.2)
Chronic renal disease
No	2940 (99.9)	1469 (99.9)	1471 (100)	0.157
Yes	2 (0.1)	2 (0.1)	0 (0)
Hypothyroidism
No	2790 (94.8)	1398 (95.0)	1392 (94.6)	0.617
Yes	152 (5.2)	73 (5.0)	79 (5.4)
Placenta problems
No	2569 (88.2)	1194 (81.2)	1402 (95.3)	<0.001
Yes	346 (11.8)	277 (18.8)	69 (4.7)
Pre-pregnancy BMI (kg/m²)
<24	2396 (81.4)	1178 (80.1)	1218 (82.8)	0.058
≥24	546 (18.6)	293 (19.9)	253 (17.2)
Assisted reproduction
No	2744 (93.3)	1363 (92.7)	1381 (93.9)	0.185
Yes	198 (6.7)	108 (7.3)	90 (6.1)
Prenatal examination
No	216 (7.3)	97 (6.6)	119 (8.1)	0.120
Yes	2726 (92.7)	1374 (93.4)	1352 (91.9)
Supplementation of folic acid before pregnancy
No	1592 (54.1)	859 (58.4)	733 (49.8)	<0.001
Partial	501 (17.0)	229 (15.6)	272 (18.5)
Full	849 (28.9)	383 (26.0)	466 (31.7)
Family history of hypertension
No	2864 (97.3)	1427 (97.0)	1437 (97.9)	0.251
Yes	78 (2.7)	44 (3.0)	34 (2.3)
Values are presented as numbers and percentages (%). PTB: preterm birth, FA: folic acid, BMI: body mass index

View popup

Table 3

- Multivariate conditional logistic regression analysis of risk factors for all preterm birth (PTB).

Variable	aOR Value	95% CI	P-value
Maternal age
<20	1.039	0.835-1.293	0.732
20-34	1.000
≥35	2.136^*	1.101-4.142	0.025
Parity
Multipara	1.230^*	1.039-1.507	0.030
Race
Han	1.000
Others	1.387	0.902-2.133	0.160
Maternal education
Middle school or below	1.459^*	1.122-1.898	0.005
High school	1.407^*	1.126-1.759	0.003
University or above	1.000
Residence during pregnancy
City	1.000
Small town	1.352^*	1.094-1.670	0.005
countryside	1.686^*	1.212-2.346	0.002
Family income monthly per person (yuan)
<2,000	1.037	0.680-1.582	0.725
2,000-10,000	0.996	0.966-1.220	0.770
>10,000	1.000
Supplementation of FA in early pregnancy
No	1.351^*	1.073-1.701	0.011
Full	1.000
Preeclampsia
Yes	9.684^*	5.967-15.716	<0.001
Smoking in pregnancy
Yes	1.691^*	1.168-2.447	0.007
Previous preterm birth
Yes	4.566^*	2.620-7.959	<0.001
diabetes mellitus in pregnancy
Yes	1.431^*	1.146-1.786	0.002
Placenta problems
Yes	11.634^*	6.661-20.320	<0.001
Pre-pregnancy BMI (kg/m²)
≥24	0.870	0.699-1.084	0.204
Assisted reproduction
Yes	1.235	0.878-1.740	0.226
Supplementation of folic acid before pregnancy
No	1.068	0.927-1.231	0.360
Partial	0.987	0.837-1.160	0.880
Full	1.000

Conditional logistic regression analysis was performed. The control group was the reference group.

↵* p<0.05 was significant. aOR value and 95% CI after adjusting other confounders (including parity, maternal age, race, maternal education, residence during pregnancy, family income monthly per person, FA supplementation in early pregnancy, FA supplementation before pregnancy, preeclampsia, smoking in pregnancy, previous preterm history, diabetes mellitus in pregnancy, and placenta problems, pre-pregnancy BMI, and assisted reproduction). CI: confidence interval, BMI: body mass index, aOR: adjusted odds ratio, FA: folic acid

View popup

Table 4

- Individual and joint effects of no FA supplementation and preeclampsia on PTB and measures of interaction.

Variable	Case/control number	aOR value	95% CI	P-value	RERI	AP	S
All preterm birth (n=1471)/control group (n=1471)
None OR₀₀	784/1001	1.000
No FA supplementation OR₀₁	488/448	1.290^*	1.026-1.623	<0.001
Preeclampsia OR₁₀	98/14	9.463	5.090-17.60	0.027
No FA supplementation + preeclampsia OR₁₁	101/8	12.138^*	5.726-25.73	<0.001	2.385	0.19	1.27
Iatrogenic preterm birth (n=655)/paired control group (n=655)
None OR₀₀	304/452	1.000
No FA supplementation OR₀₁	165/190	1.385	0.938-2.047	0.180
Preeclampsia OR₁₀	91/8	19.680^*	8.462-45.77	<0.001
No FA supplementation + preeclampsia OR₁₁	95/5	23.412^*	8.882-60.71	<0.001	3.347	0.14	1.18
Spontaneous preterm birth (n=816)/paired control group (n=816)
None OR₀₀	480/549	1.000
No FA supplementationOR₀₁	323/258	1.353^*	1.009-1.814	0.043
Preeclampsia OR₁₀	7/6	1.140	0.317-4.106	0.841
No FA supplementation + preeclampsia OR₁₁	6/3	2.056	0.471-8.984	0.338	-	-	-

Conditional logistic regression analysis was carried out. The control group was the reference group. Taking preeclampsia and folic acid supplementation in early pregnancy as independent variables, patients were divided into 4 groups: no preeclampsia and folic acid supplementation (0.4-0.8 mg/d for 12 weeks) in early pregnancy (OR₀₀), no preeclampsia and no FA supplementation in early pregnancy (OR₀₁), preeclampsia and folic acid supplementation (0.4-0.8 mg/d for 12 weeks) in early pregnancy (OR₁₀), preeclampsia and no FA supplementation in early pregnancy (OR₁₁), no preeclampsia and FA supplementation (0.4-0.8 mg/d for 12 weeks) in early pregnancy (OR₀₀) were used as the reference group. Adjusted ORs (aOR) were calculated by adjusted confounding factors, maternal age, parity, maternal education, residence, smoking in pregnancy, previous preterm birth, diabetes mellitus in pregnancy, placenta problems, supplementation of folic acid before pregnancy, assisted reproduction, pre-pregnancy BMI.

↵* p<0.05 was significant.FA: folic acid, BMI: body mass index, RERI: excess relative risk of interaction effect, AP: proportion attributable to interaction, S: synergy index, CI: confidence interval