Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study
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Sengpiel et al. BMC Pregnancy and Childbirth 2014, 14:375 http://www.biomedcentral.com/1471-2393/14/375 RESEARCH ARTICLE Open Access Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study Verena Sengpiel1*, Jonas Bacelis1, Ronny Myhre2, Solveig Myking2, Aase Serine Devold Pay3, Margaretha Haugen4, Anne-Lise Brantsæter4, Helle Margrete Meltzer4, Roy Miodini Nilsen5, Per Magnus6, Stein Emil Vollset7, Staffan Nilsson8 and Bo Jacobsson1,2 Abstract Background: Health authorities in numerous countries recommend periconceptional folic acid supplementation to prevent neural tube defects. The objective of this study was to examine the association of dietary folate intake and folic acid supplementation during different periods of pregnancy with the risk of spontaneous preterm delivery (PTD). Methods: The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 66,014 women with singleton pregnancies resulting in live births in 2002–2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until pregnancy week 24. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4–5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,755). Results: The median total folate intake was 313 μg/d (interquartile range IQR 167–558) in the overall population and 530 μg/d (IQR 355–636) in the supplement users. Eighty-five percent reported any folic acid supplementation from
Sengpiel et al. BMC Pregnancy and Childbirth 2014, 14:375 Page 2 of 12 http://www.biomedcentral.com/1471-2393/14/375 Background effect of the maternal folate status on the gestational Folate is a B-vitamin essential for one-carbon metabol- length or the risk of spontaneous PTD [23-25]. The ism and takes part in amino acid metabolism as well as comparability and generalizability of these earlier stud- DNA synthesis, repair and methylation [1,2]. Women ies, which focused on the association of folate status are especially susceptible to folate deficiency during and folic acid supplementation with pregnancy out- pregnancy, which is a period of rapid fetal growth, organ come, is limited because folic acid supplementation was differentiation and high rates of cell division [1,3,4]. assessed without considering other folate sources, the Since the 1950s, folic acid supplementation has been study populations had different levels of dietary folate known to prevent megaloblastic anemia during preg- intake, inadequate sample sizes, limited adjustment for nancy [5]. In the 1990s, large randomized trials demon- important confounders, and/or retrospective study de- strated that periconceptional folic acid supplementation signs with folate data collection only after delivery [1,4]. can prevent neural tube defects (NTDs) in the newborn Although PTD is a heterogeneous pregnancy outcome infant [6-8]. Today, national health authorities in many with different etiologies (early vs. late or iatrogenic vs. countries recommend periconceptional folic acid sup- spontaneous), previous studies have mostly treated PTD as plementation, and some countries have introduced one entity, obscuring the differences in risk among PTD mandatory folate fortification of foods [1,3,4,9,10]. In subtypes [26,27]. Norway, folic acid supplementation of 400 μg/d is rec- The Norwegian Mother and Child Cohort Study (MoBa) ommended from the time of planning a pregnancy to can meet a number of these challenges in study design, a gestational week 12 [2,11], as is a daily folate intake of requirement for addressing the inconsistencies in the field. 500 μg/d. This is in line with the Nordic Nutrition Rec- MoBa includes more than 106,000 pregnancies, enabling ommendations [2]. the investigation of common complex pregnancy out- Maternal folate status has also been associated with comes such as PTD. A detailed prospective assessment of other adverse pregnancy outcomes such as preeclamp- folic acid supplementation starting from 6 months before sia, malformations such as orofacial clefts, spontaneous conception throughout pregnancy, data regarding dietary abortion, fetal death, fetal growth restriction and pre- folate intake and comprehensive information about life- term delivery (PTD), although these results still remain style habits, health and socioeconomic status provide a inconclusive [1]. unique opportunity to study the association between folate PTD, defined by the World Health Organization intake and PTD. For example, the effect of folic acid sup- (WHO) as birth occurring before 37 weeks of gestation, plementation can be compared between women with low is considered a major global health problem and is and high dietary folate intakes. By taking into account the strongly associated with neonatal mortality as well as amount of dietary folate and folic acid supplementation short- and long-term morbidity [12-14]. Spontaneous during different periods of pregnancy, it might be possible PTD is a common, complex condition with a prevalence to define the folic acid supplementation scheme most of approximately 7% in the Norwegian population [15]. likely to affect PTD risk. However, the effect of any single environmental factor The aim of this study was to examine the association is difficult to measure without large-scale studies [15]. of maternal folate intake from both supplemental and Modern obstetrics are still not able to predict, prevent dietary sources with the risk of spontaneous PTD, with or treat PTD [16]. Progesterone substitution, the only sub-analyses of early and late spontaneous PTD. The as- promising intervention identified to date, has been shown sociation of folic acid supplementation with PTD was to reduce the chance of spontaneous PTD in high-risk studied in a stratified sample of women with low and pregnancies, but such cases account for only a small pro- high dietary folate intakes (
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status, lifestyle behavior and diet at gestational weeks sold in Norway were registered based on information
15–17 (Q1) and 30 (Q3). At week 22, they completed a provided by the respective manufacturer, whereas nutri-
food frequency questionnaire (FFQ). All questionnaires tional information concerning dietary supplements bought
are available from the homepage of the Norwegian Insti- from the Internet or abroad were obtained from the man-
tute of Public Health [28]. The present study used data ufacturer’s or supplier’s homepage. A data program con-
from version 6 of the quality-assured data files made nected to the Access database read all food supplements
available for research in 2011. The MoBa database is recorded by the MoBa participants. The process of extract-
linked to pregnancy and birth records from the Medical ing dietary and supplement data is described in detail else-
Birth Registry of Norway (MBRN) [29]. Informed written where [33,34].
consent was obtained from each participant. The Regional Dietary folate was defined as 60% of the reported fol-
Committee for Medical Research and the Norwegian Data ate intake from foods, as only approximately 60% may
Inspectorate approved the study. be biologically accessible in comparison to that from
Of 106,707 pregnancies included in the MoBa version the synthetic folic acid in supplements [1,3]. The total
6, 103,921 pregnancies resulted in live-born singletons. folate intake was thus calculated as supplemental folic
Complete data for all 3 questionnaires including infor- acid +0.6 × folate intake from foods.
mation about folate intake were available for 81,329 The daily folate intake was also categorized into 4
pregnancies. Women reporting improbable energy in- groups: 1000 μg/d.
were included in the study. Pregnancies with a gestational
length of 42+6 weeks were excluded from fur- Timing of folic acid supplementation
ther analysis, leaving 75,873 remaining. If a woman par- The women reported their folic acid supplement use
ticipated for more than one pregnancy, only her first from 26 weeks before conception until gestational week
pregnancy enrolled was included, leaving 66,014 preg- 24 in 4-week intervals, including the frequency of
nancies for analyses. supplementation. A woman was defined as a folic acid
supplement user if she reported any use of folic acid –
Outcome containing supplements for more than once a week in a
The gestational age in days was determined with a registered 4-week period. Folic acid may be consumed
second-trimester ultrasound in 98.4% of the pregnancies either in the form of a folic acid supplement alone or as
and was based on the last menstrual period in the part of multivitamins. The most commonly used folic
remaining cases. Spontaneous PTD was defined as birth acid supplements for pregnant women in Norway con-
after preterm labor or pre-labor rupture of the mem- tain 400 μg of folic acid, while the most commonly used
branes between 22+0 and 36+6 weeks. To distinguish be- multivitamin supplements contain 200 μg of folic acid.
tween early and late spontaneous PTDs, we used the For this study, the start of folic acid supplementation
following gestational time-windows: early (22+0-33+6) was categorized as start during 26–9 weeks before con-
and late (34+0-36+6) PTD. ception, start during 8–0 weeks before conception, and
no preconceptional folic acid supplementation.
Exposure
Amount of folate intake Covariates
The amount of folate intake was calculated from the Covariates were chosen a priori based on the available
MoBa FFQ, a semi-quantitative questionnaire designed literature. Information regarding the maternal age at de-
to yield information regarding the dietary habits and in- livery as well as the child’s sex is available from the
take of dietary supplements during the first 5 months of MBRN. Parity was based on data from both the MoBa
pregnancy. The questionnaire data were read optically, and MBRN and based on the number of previous preg-
and the nutrient and energy intakes were calculated nancies of ≥22+0 weeks’ duration. Marital status was
using FoodCalc [31] and the Norwegian Food Compos- defined as either married/cohabitant or not. The self-
ition Table [32]. For the calculation of nutrients in the reported pre-pregnancy heights and weights were used
dietary supplements, an Access database containing the to calculate the pre-pregnancy body mass index (BMI)
nutrient values of more than 1,000 dietary supplements and were grouped according to the WHO classification
was created and continuously updated using Microsoft as underweight (Sengpiel et al. BMC Pregnancy and Childbirth 2014, 14:375 Page 4 of 12
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Maternal education was categorized as ≤12 y, 13–16 y had higher education levels and family incomes. Women
and ≥17 y. The history of previous PTD before 37+0 weeks having experienced PTD had significantly lower total fol-
of gestation, and the history of spontaneous abortion, as ate intakes. While women with a history of spontaneous
registered in the MBRN, were taken into account as di- abortion had more often started folic acid supplementa-
chotomous variables in regression models. Women re- tion early, no comparable pattern in women with a his-
ported smoking habits during pregnancy in Q1 and tory of PTD was found (Table 1).
were categorized as non-smokers, occasional or daily Figure 1 illustrates the pattern of folic acid supplementa-
smokers. The alcohol intake from different sources was tion in the study population compared to vitamin A supple-
self-reported in the FFQ (glasses/d, week or month) and mentation (as a proxy for multivitamin consumption) over
calculated as g/d. The household income was classified as the course of pregnancy. 85% of all women in the study re-
both the participant and her partner having 5000 μg/d, 610
multivitamin preparations. In MoBa more than 99% of the consuming >1000 μg/d (1%), 6,834 consuming >500 μg/d
participants are of Caucasian ethnicity; hence, ethnicity (10%), 10,681 consuming >400 μg/d (16%), 27,183 consum-
was not a relevant confounder. ing >200 μg/d (41%) and 34,234 consuming >100 μg/d
(52%). Among supplement users, the median daily folic acid
Statistical methods supplementation was 400 μg/d (interquartile range IQR
All statistical analyses were performed using IBM SPSS 200–429). As presented in Table 2, folic acid from supple-
Statistics 22 and R 2.13.1 software. Total dietary folate ments was the main folate source in supplement users,
intake from foods and supplements (median (IQR)) in while the main source was dietary folate in the whole popu-
relation to the maternal characteristics was studied with lation. There is no mandatory folate fortification of foods in
the Kruskal-Wallis test. The start of folic acid supple- Norway, and only 3% (n = 1,946, not adjusted for bioavail-
mentation in relation to the maternal characteristics was ability) of the study population reached the Nordic Nutri-
studied with Pearson’s chi-squared test. The association tion Recommendation of 500 μg/d with their dietary folate
of total dietary folate intake and spontaneous PTD was intake. Of the study participants, 44% (n = 28,959, not ad-
estimated as a hazard ratio (HR) with a 95% confidence justed for bioavailability) achieved the recommended levels
interval (CI) by using Cox regression both in an un- with their total folate intake.
adjusted model and adjusted for the above-mentioned
covariates. In these models, the event was defined as a Folate intake from different sources and risk for
spontaneous PTD; all iatrogenic deliveries and deliver- spontaneous PTD
ies after the preterm (≥37+0 weeks) or early preterm The median gestational age in this study population was
(≥34+0 weeks) period were censored. The proportional 281 days (IQR 274–287), with 2,906 (4%) cases of PTD
hazards assumption was investigated by testing and and 1,755 cases of spontaneous PTD (2.7%). Of these,
inspecting scaled Schoenfeld residuals using R function 334 babies were delivered before 34+0 weeks of gestation
cox.zph [36]. Statistical significance was assumed for 2- (0.5%). Thus the overall PTD rate in our study popula-
sided p-values ofSengpiel et al. BMC Pregnancy and Childbirth 2014, 14:375 Page 5 of 12
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Table 1 Folate variables and maternal characteristics
Total folate intake (μg/d) Initiation of preconceptional folic acid supplementation, n (%)
n (%) Median (IQR) p1 >8 w 0-8 w No p2
Total 66014 (100) 313 (167–558) 16023 (24) 12877 (20) 37114 (56)Sengpiel et al. BMC Pregnancy and Childbirth 2014, 14:375 Page 6 of 12 http://www.biomedcentral.com/1471-2393/14/375 categorized according to the former WHO recom- A history of earlier adverse pregnancy outcome could mendation for women (>170 μg/d), the current Nordic be a motive for the early initiation of folic acid supple- Nutrition Recommendations for pregnant women mentation in subsequent pregnancies. However, the ana- (>500 μg/d) and the tolerable upper limit (for folic acid lysis of the subgroup of women being pregnant the first supplementation:
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Table 2 Folate intake from diet and supplements
All Spontaneous delivery 37+0- 42+6 Spontaneous PTD 22+0-36+6
Folate (μg/d) Median IQR Median IQR Median IQR
All women n = 66014 n = 51141 n = 1755
Diet 157 (126–196) 157 (126–196) 157 (126–196)
Supplements 143 (0–400) 143 (0–400) 171 (0–400)
Total intake 313 (167–558) 312 (167–558) 322 (167–568)
Supplement users n = 39600 n = 30684 n = 1056
Diet 158 (127–197) 158 (127–197) 159 (128–198)
Supplements 400 (200–429) 400 (200–429) 400 (200–457)
Total intake 530 (355–636) 530 (355–634) 541 (369–651)
Folic acid supplementation, dietary and total folate intake during the first half of pregnancy (FFQ data) for all 66,014 participants, as well as in folic acid
supplement users (n = 39,600), from the Norwegian Mother and Child Cohort Study (2002–2009).
supplementation on the spontaneous PTD risk, support a 1 year or longer [21] or third-trimester folic acid supple-
number of earlier observational studies [38-43] and RCTs mentation [22], raising questions about extended supple-
[6,44,45]. A reanalysis of a previous Cochrane review, and mentation schemes compared to the NTD prevention
one of the largest RCTs, a recent meta-analysis of all RCTs scheme. Folic acid supplementation more than a 1 year be-
published to date as well as the most recent Cochrane re- fore becoming pregnant is not registered in MoBa, but
view based on 3 available trials, showed no association of data for the earliest interval (26–9 weeks before concep-
the maternal folate status with the gestational length or tion) suggest an adverse effect of longtime folic acid sup-
the risk of PTD [23-25]. Extensive supplementation with plementation on the risk of spontaneous PTD. Though
multivitamins with a major folic acid component was asso- third trimester folic acid supplementation is registered in
ciated with an increased risk of PTD in a study by Alwan MoBa, we chose to not include third trimester supplemen-
et al. [38]. When analyzing data from the US National tation as the early PTDs already have occurred at different
Birth Defects Study, Shaw et al. found a lower risk of PTD time points during this period, so that we were not able to
for women starting supplementation during pregnancy as retrace the findings by Czeizel et al. [22].
compared to preconceptional supplementation start [43]. One possible explanation for these conflicting results
However, results are conflicting as summarized in the could be the dosage of folic acid. While most of the
review by Mantovani et al. [27]. A protective effect of studies finding an association with gestational length or
folic acid supplementation was supported by a modest PTD were based on high doses of folic acid (≥5000 μg/d
reduction in the PTD rate after the introduction of folate [20,22,46], ≥2500 μg/d [22,47] and ≥500 μg/d [48-50]),
fortification of foods [9]. Some recent observational studies only 2 women in our study population consumed as
have found that folic acid supplementation reduces the much as 5000 μg/d of supplemental folic acid, while only
risk of PTD [20-22]. In some cases, this association was 10% consumed >500 μg/d and 16% consumed >400 μg/
found for preconceptional folic acid supplementation for d. However, the Hungarian RCT, one of the biggest per-
formed so far, did not find any effect of a high dosage of
Table 3 Folate intake from different sources and risk of 800 μg/d of periconceptional folic acid supplementation
spontaneous preterm delivery (PTD) on PTD [6]. Unfortunately, the folic acid dosage was not
Unadjusted Adjusted2 indicated in all of the studies [21,37].
Folate (μg/d) HR 1
(95% CI) p HR1 (95% CI) p
The assessment of folate intake from supplementation
alone or when studying populations with different dietary
Diet 1.00 (0.61; 1.65) 0.61 1.00 (0.61; 1.65) 0.54
folate intakes are additional factors compromising com-
Supplements 1.00 (1.00; 1.00) 0.25 1.00 (1.00; 1.00) 0.53
parability between studies. While recent US studies are
Total intake 1.00 (1.00; 1.00) 0.22 1.00 (1.00; 1.00) 0.46 performed against the background of mandatory folate for-
Amount of folic acid supplementation, dietary and total folate intake (FFQ tification of food [21,43], other studies have examined sup-
data) and hazard ratios for spontaneous PTD (22+0-36+6 weeks, n = 1,755). Cox
regression for 66,014 participants in the Norwegian Mother and Child Cohort
plementation effects in folate-deficient populations [46].
Study (2002–2009). Iatrogenic deliveries have been censored in the Few studies have assessed the effects of both dietary folate
regression model. and folic acid supplementation separately [43] or com-
1
HR per 500 μg extra folate/d.
2
Cox regression, adjusted for maternal age, prepregnancy BMI, parity, history bined [20,49,51], and adjustments for bioavailability are
of PTD and spontaneous abortion, child’s sex, smoking habits and alcohol rare. In this Norwegian study population, only 3% of
consumption during pregnancy, maternal education, marital status, household
income, energy intake. Mutual adjustment for dietary and supplemental
the participants reached the Nordic Nutrition Recom-
folate intake. mendation of 500 μg/d with their dietary folate intake,Sengpiel et al. BMC Pregnancy and Childbirth 2014, 14:375 Page 8 of 12
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Table 4 Initiation of preconceptional folic acid supplementation and risk of spontaneous preterm delivery (sPTD)
sPTD Initiation of folic acid supplementation Unadjusted Adjusted1 Adjusted2
n HR (CI) p HR (CI) p HR (CI) p
All No 964 1 1 1
0-8 w preconception 313 0.93 (0.82; 1.06) 0.28 0.99 (0.87; 1.13) 0.89 1.01 (0.88; 1.16) 0.88
>8 w preconception 478 1.15 (1.03; 1.29) 0.01 1.18 (1.05; 1.32) 0.005 1.20 (1.06; 1.36) 0.004
Early No 169 1 1 1
0-8 w preconception 57 0.97 (0.72; 1.31) 0.84 1.07 (0.79; 1.45) 0.67 1.04 (0.76; 1.43) 0.81
>8 w preconception 108 1.48 (1.16; 1.89) 0.001 1.60 (1.24; 2.06) 8 w preconception 370 1.08 (0.96; 1.22) 0.22 1.09 (0.96; 1.24) 0.19 1.12 (0.98; 1.29) 0.11
+0 +6
Initiation of preconceptional folic acid supplementation (Q1 data) and hazard ratios (HR) for spontaneous PTD (n = 1,755 for 22 -36 weeks, n = 334 for early
(22+0-33+6 weeks), n = 1,421 for late (34+0-36+6 weeks)). Cox regression for 66,014 participants in the Norwegian Mother and Child Cohort Study (2002 – 2009).
Iatrogenic deliveries have been censored in the regression model.
1
Cox regression, adjusted for maternal age, prepregnancy BMI, parity, history of PTD and spontaneous abortion, child’s sex, smoking habits and alcohol
consumption during pregnancy, maternal education, marital status, household income, energy intake and dietary folate intake.
2
Adjustment as above as well as for first-trimester folic acid supplementation and preconceptional and first-trimester vitamin A supplementation.
and 44% of the participants achieved the recommended is well established that women with high levels of educa-
level with their dietary folate and supplemental folic tion, privileged socioeconomic status and healthier overall
acid intake. After stratification for dietary folate intake, diets are more likely to use supplements during pregnancy
the early initiation of folic acid supplementation was [52-54] and less likely to experience PTD than women
significantly associated with spontaneous PTD in the without these characteristics. Some observational studies
subgroup of women with low but not high dietary folate failed to adjust for these confounders, and the effect at-
intakes. There were no significant associations between tributed to folic acid supplementation might in fact be
high total folate intakes and PTD risk in the MoBa confounded by overall health and lifestyle behaviors. While
study population. the strength of the significance was moderate, the asso-
In observational studies, confounding is always an issue ciation with the early onset of folic acid supplementa-
when assessing the association of a single environmental tion in the current study remained significant even
factor with a complex outcome like PTD. For example, it after adjustment for maternal characteristics such as
Table 5 Timing of folic acid supplementation and risk of spontaneous preterm delivery (PTD)
Time of folic acid supplementation sPTD Unadjusted Adjusted1
n HR (CI) p HR (CI) p
All >8 w preconception 478 1.17 (1.06; 1.30) 0.003 1.17 (1.04; 1.32) 0.01
0-8 w preconception 648 1.01 (0.92; 1.12) 0.80 1.01 (0.90; 1.13) 0.84
1st trimester 1326 0.94 (0.84; 1.05) 0.26 0.89 (0.79; 1.00) 0.05
2nd trimester 869 1.10 (1.00; 1.21) 0.04 1.08 (0.98; 1.19) 0.11
Early >8 w preconception 108 1.49 (1.19; 1.88) 0.001 1.51 (1.16; 1.97) 0.002
0-8 w preconception 133 1.15 (0.92; 1.43) 0.23 1.03 (0.80; 1.34) 0.81
1st trimester 262 1.11 (0.85; 1.44) 0.45 0.99 (0.74; 1.32) 0.95
2nd trimester 173 1.21 (0.97; 1.49) 0.09 1.12 (0.89; 1.39) 0.34
Late >8 w preconception 370 1.10 (0.98; 1.24) 0.10 1.10 (0.97; 1.26) 0.15
0-8 w preconception 515 0.98 (0.88; 1.09) 0.69 1.00 (0.88; 1.13) 0.94
1st trimester 1064 0.91 (0.81; 1.03) 0.13 0.87 (0.76; 1.00) 0.04
2nd trimester 696 1.08 (0.98; 1.20) 0.13 1.08 (0.97; 1.20) 0.17
Folic acid supplementation at different times (Q1 and Q3 data) and hazard ratios (HR) for spontaneous PTD (n = 1.755 for 22+0-36+6 weeks, n = 334 for early
(22+0-33+6 weeks), n = 1,421 for late (34+0-36+6 weeks)) as compared to no intake at that time of pregnancy. Cox regression for 66,014 participants in the
Norwegian Mother and Child Cohort Study (2002 – 2009). Iatrogenic deliveries have been censored in the regression model.
1
Cox regression, adjusted for maternal age, prepregnancy BMI, parity, history of PTD and spontaneous abortion, child’s sex, smoking habits and alcohol
consumption during pregnancy, maternal education, marital status, household income, energy intake and dietary folate intake. Mutual adjustment for folic acid
supplementation at other time points.Sengpiel et al. BMC Pregnancy and Childbirth 2014, 14:375 Page 9 of 12 http://www.biomedcentral.com/1471-2393/14/375 socioeconomic and life-style parameters as well as ob- Strengths and weaknesses stetric anamnesis. With a sample size of 66,014 pregnancies, this was a well- Associations with the early start of supplementation powered study for investigating the association of folate in- should be studied with particular caution. The early start take and spontaneous PTD. Due to the large study sample, of folic acid supplementation might partially identify a there were 1,755 cases defined as spontaneous PTD and group of women with a history of adverse pregnancy out- 334 and 1,421 cases in the subgroups of early and late comes who want to optimize conditions for their current spontaneous PTD, respectively. The estimation of the ges- pregnancy. As presented in Table 1, women who had pre- tational length by the second-trimester ultrasounds and viously experienced spontaneous abortions were more the definition of a clear PTD phenotype – spontaneous on- likely to initiate folic acid supplementation early in their set of delivery between 22+0 and 36+6 weeks of gestation - subsequent pregnancies. However, the same association of distinguish this study. the early initiation of folic acid supplementation and spon- The MoBa participation rate is 38.5%, and a demo- taneous PTD was found in women being pregnant the first graphic comparison with the MBRN in 2002 showed time. Folic acid supplementation starting more than that single women and women
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157 μg/d corrected for bio-availability, uncorrected Statement of financial support: This work was supported by grants from the
262 μg/d) and supplemental folic acid (median 143 μg/d) Norwegian Research Council (FUGE 183220/S10, FRIMEDKLI-05 ES236011), the
Swedish Medical Society (SLS 2008–21198) and Swedish government grants to
in this healthy study population. researchers in public health service (ALFGBG-2863, ALFGBG-11522, ALF-ST
The initiation of folic acid supplementation more than FoUU/Sahlgrenska University Hospital, Gothenburg), Stiftelsen Sigurd och
8 weeks prior to conception was associated with an in- Elsa Goljes Minne (LA2011-0489). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the
creased risk for overall and early spontaneous PTD in manuscript.
both the overall analyses and in the strata of women
with low dietary folate intake. Author details
1
Department of Obstetrics and Gynaecology, Sahlgrenska Academy,
Even if MoBa allows adjustment for a variety of con- Sahlgrenska University Hospital/Östra, Göteborg SE-416 85, Sweden.
founders, the presence of residual confounding cannot 2
Department of Genes and Environment, Division of Epidemiology,
be ruled out. Furthermore, our results require careful in- Norwegian Institute of Public Health, Nydalen, P.O. Box 4404, Oslo NO-0403,
Norway. 3Department of Obstetrics and Gynecology, Women and Children’s
vestigation regarding dosage and timing of folic acid Division, Oslo University Hospital, Nydalen, P.O. Box 4950, Oslo NO-0424,
supplementation, such as in the form of an RCT, before Norway. 4Department of Exposure and Risk Assessment, Division of
discussing a change of the current guidelines. Environmental Medicine, Norwegian Institute of Public Health, Nydalen, P.O.
Box 4403, Oslo NO-0403, Norway. 5Department of Global Public Health and
Primary Care, University of Bergen, Bergen NO-5018, Norway. 6Division of
Additional files Epidemiology, Norwegian Institute of Public Health, P.O. Box 4403, Oslo
NO-0403, Norway. 7Norwegian Institute of Public Health and University of
Bergen, Kalfarveien 31, Bergen NO-5018, Norway. 8Mathematical Sciences,
Additional file 1: Table S1. Folate intake according to official Chalmers University of Technology, Göteborg SE-412 96, Sweden.
recommendations and risk of spontaneous preterm delivery (PTD).
Additional file 2: Figure S1a. Initiation of preconceptional folic acid Received: 6 June 2014 Accepted: 16 October 2014
supplementation and risk of spontaneous PTD. Initiation of
preconceptional folic acid supplementation (Q1 data) and cumulative risk
of spontaneous PTD (22+0-36+6 weeks, n = 1,755). Cox regression for
66,014 participants in the Norwegian Mother and Child Cohort Study References
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Competing interests
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doi:10.1186/s12884-014-0375-1
Cite this article as: Sengpiel et al.: Folic acid supplementation, dietary
folate intake during pregnancy and risk for spontaneous preterm
delivery: a prospective observational cohort study. BMC Pregnancy and
Childbirth 2014 14:375.
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