Folic Acid Supplementation and Preterm Birth: Results from Observational Studies

Table 1

Dose, period, and effect of FA supplementation on PTB in recent observational studies.

Author; Year; Reference; Type of study	Study period	𝑁 women	Supplementation		Supplementation period	Recruitment	Birth; outcomes	PTB/; population	PTB; OR (95% CI)
Papadopoulou et al.; 2013; [63]; Cohort study	2007-2008	1,279	No use		Early to midpregnancy	14.6±3.2 wk; (14–18)	PTB; sPTB; LBW; SGA	26/157	Reference^a
			FA ± iron	ED 5 mg				90/849	0.69 (0.44–0.99); sPTB 0.57 (0.33–0.99)
				6–15 mg				30/273	0.72 (0.41–1.25); sPTB 0.71 (0.37–1.34)
Shaw et al.; 2011; [66]; Controls of; case-control study	1998–2005	5,912	MV with FA	Dose not reported	1 month before conception; 1st trimester; 2nd-3rd trimester; Sporadic use; No use, before or during pregnancy	6 wk after estimated delivery–24 months after delivery	PTB; LBW	158/1,697	Reference^b
								197/2612; 29/380; 62/826; 28/293	0.69 (0.52–0.92); 0.54 (0.31–0.93); 0.70 (0.46–1.04); 0.86 (0.49–1.50)
Catov et al.; 2011; [69]; Cohort study	1997–2003	35,897	No use		4 wk before-8 wk after last menstrual period	11.1±3.9 wk; (5–24 wk)	PTB; SGA	604/11,503	Reference^c
			MV with FA	200 mcg				1,013/21,785	Any use, all women: 0.89 (0.80–0.99)
									Any use, BMI < 25: 0.84 (0.73–0.95)
									Any use, BMI ≥ 25: 1.03 (0.84–1.26)
			FA	200 mcg				137/2,609	1.00 (0.91–1.11)
Alwan et al.; 2010; [67]; Cohort study	2003–2006	1,234	FA/MV with FA	Dose not reported	1st trimester; 2nd trimester; 3rd trimester	8–12 wk	PTB; BW; SGA	1,340*; 229; 82	1.3 (0.6–2.7)^d; 1.8 (0.8–4.1); 3.4 (1.2–9.6)
Czeizel et al.; 2010; [64] Controls of case-control study	1980–1996	38,151	No use		II and III trimesters	after birth	PTB; LBW	1,792/16,177; 1,461/19,102; 44/685; 64/1,410	Reference^e; 0.68 (0.63–0.73); 0.63 (0.46–0.86); 0.40 (0.31–0.51)
			FA	ED 5.6 mg
			MV with FA	ED 0.85 mg
			MV with FA + FA	ED 3.7 mg
Bukowski et al.; 2009; [68]; Cohort study	1999–2002	34,480	No use		Preconception; start	1st trimester	sPTB; SGA; PE; Abruptio; placentae	790/15,259	Reference^f
			FA ± MV	Dose not	<1 Y			558/12,444	20–28 wk: 0.72 (0.40–1.28)
				reported					28–32 wk: 0.73 (0.47–1.13)
									32–37 wk: 0.93 (0.83–1.06)
					>1 Y			311/6,777	20–28 wk: 0.31 (0.11–0.90)
									28–32 wk: 0.53 (0.28–0.99)
									32–37 wk: 0.99 (0.85–1.15)
Timmermans et al.; 2009; [65]; Cohort study	2002–2006	6,353	No use			15.4 wk; (10.2–24.8 wk)	PTB; LBW; SGA	1,877	Reference^g
			FA	0.4–0.5 mg	Preconception start			2,493	0.88 (0.63–1.21)
					Start before 8 wk of gestational age			1,983; PTB not reported	0.75 (0.55–1.02)

Suppl.: supplementation; wk: weeks; ED: estimated dose; MV: multivitamin; sPTB: spontaneous preterm birth; PE: preeclampsia; BW: birth weight; LBW: low birth weight; SGA: small for gestational age. aAdjusted for maternal age, education, Greek origin, prepregnancy BMI (kg/m²), smoking status, parity, and iron intake from supplements. bAdjusted for other two sources of folate, infant birth weight, smoking, alcohol use, race/ethnicity, maternal education, and maternal age. cAdjusted for maternal age, parity, BMI, smoking, and sociooccupational status. ∗Women taking FA/MV. 55 total PTB reported. dAdjusted for salivary cotinine levels, self-reported alcohol intake, maternal age, maternal vegetarian diet, ethnicity, baby’s sex, parity, Index of Multiple Deprivation score, educational attainment, past history of miscarriage, and long-term chronic illness in an unconditional logistic regression model. eAdjusted for maternal age, socioeconomic status, and birth order. fAdjusted for maternal age, body mass index, race and ethnicity, educational level, marital status, smoking, parity, and history of prior preterm birth and recruitment center. gAdjusted for gestational age at birth (not prematurity), maternal age, height, weight, parity, ethnicity, fetal gender, educational level, and smoking.