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Maternal and pediatric nutrition

Folic acid supplementation and fecundability: a Danish prospective cohort study

Abstract

Background/Objectives:

Periconceptional folic acid (FA) supplementation reduces the risk of neural tube defects and has been associated with ovulatory function. However, only two studies have associated supplementation with multivitamins (MVs) that contained FA with increased pregnancy rates. We aimed to examine the association between FA supplementation (obtained either through single FA tablets or through MVs) and fecundability.

Subjects/Methods:

A prospective cohort study of 3895 Danish women who were planning a pregnancy between 2007 and 2011. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) in relation to FA supplementation (either through single FA tablets or MV) using a proportional probabilities regression model, with adjustment for potential socio-demographic, reproductive and lifestyle confounders. In stratified analyses, we also estimated FR with 95% CI in relation to FA supplementation for women with regular and irregular cycles, respectively, and for women with short (<27 days), medium (27–29 days) and long cycles (30 days), respectively.

Results:

FA supplementation was associated with increased fecundability (FR=1.15, 95% CI=1.06–1.25), compared with non-use. The adjusted FRs for FA supplement use relative to non-use were 1.35 (95% CI=1.12–1.65) and 1.11 (95% CI=1.01–1.22) for women with irregular and regular cycles, respectively, and 1.36 (95% CI=0.95–1.95), 1.10 (95% CI=0.98–1.22) and 1.24 (95% CI=1.10–1.41) for women with short (<27 days), medium (27–29 days) and long cycles (30 days), respectively.

Conclusions:

FA supplementation was associated with increased fecundability, and this association appeared to be stronger among women with irregular cycles and among women with either short or long cycle length.

Introduction

Periconceptional folic acid (FA) supplementation is known to reduce the risk of neural tube defects1, 2 and other congenital malformations.3, 4 In many countries, including Denmark, women planning to conceive therefore are advised to take a daily supplement of 400 μg of FA.5

Folates in the form of tetrahydrofolates are essential cofactors for several one-carbon unit transfer reactions, including the biosynthesis of methionine from homocysteine, and are required for the biosynthesis of purines, thymidylate and DNA.6, 7 Although little is known about the possible beneficial effects of FA supplementation on fecundability (defined as the probability of conceiving during a single menstrual cycle with unprotected intercourse), inadequate intake of dietary folate or FA supplements may have an essential role in the hormonal balance and follicular development.6, 7, 8, 9, 10 Cross-sectional studies of women undergoing in vitro fertilisation have associated FA supplementation with increased folate and decreased homocysteine concentrations in the follicular fluid and with a higher degree of oocyte maturity.11, 12 In a follow-up study of women without a history of infertility, Chavarro et al.13 reported that regular use of multivitamins (MVs; including FA) was inversely associated with ovulatory infertility. Also, Gaskins et al.14 reported that a diet high in synthetic FA reduced the risk of anovulatory cycles among women without a history of infertility. Finally, preconceptional FA and MV use have been associated with increased progesterone levels in the luteal phase,14, 15 improved menstrual cycle regularity16 and normalisation of cycle length,15 which have all been associated with fecundability.17, 18

Two randomised trials, one enroling 35 women with fertility problems15 and one enroling 7905 women without fertility problems,19 reported higher pregnancy rates among users of MV (including FA) compared with placebo tablets, indicating that FA supplementation to some extent increase fecundability. Although national surveys of dietary habits have indicated insufficient dietary folate intake among women of child-bearing age,20 Denmark has not introduced a mandatory national programme to fortify food with FA. Thus, whether fecundability can be improved by FA supplementation is of particular public health interest. In this study, we evaluated the association between FA supplementation, obtained either through single FA tablets or through MVs and fecundability among women enroled in a Danish Internet-based pregnancy planning study.

Subjects and methods

The Danish pregnancy planning study

Data for this study were collected as part of the Danish Pregnancy Planning Study (‘Snart-Gravid.dk’), an Internet-based prospective cohort study of women planning a pregnancy. Recruitment methods have been described previously.21, 22, 23 Briefly, enrolment and data collection via self-administered questionnaires were conducted on the study website (https://www.snartforaeldre.dk/). Before enrolment, potential participants read a consent form and completed an online screening questionnaire to confirm eligibility. Participants also provided a valid e-mail address and their Civil Registration Number.

Eligible women were invited to complete a baseline questionnaire and bimonthly follow-up questionnaires for 12 months or until conception occurred. The baseline questionnaire included questions on socio-demographic background, reproductive and medical history and lifestyle and behavioural factors, including the use of vitamins and other supplements. Follow-up questionnaires collected information on the date of the last menstrual period (LMP), pregnancy status and lifestyle variables such as vitamin use, frequency of intercourse and smoking status––that is, variables that may change over time.

Study population and study period

The Snart-Gravid.dk study included women who met the following criteria: Danish residents, aged 18–40 years, in a stable relationship with a male partner, attempting to conceive and not receiving fertility treatment. From 1 June 2007 to 18 August 2011, 5920 eligible women enroled in the study. In the present analysis, we excluded women who had tried to conceive for more than six cycles at the time of study entry (n=1152), as women may change their lifestyle behaviours the longer they have been trying to conceive. In addition, we excluded women who did not complete at least one follow-up questionnaire (n=579) and women who provided insufficient or implausible information about the date of their LMP or the date of their first pregnancy attempt (n=294). Thus, the final study population comprised 3895 women (Figure 1).

Figure 1
figure1

Flow chart and study outcomes.

Assessment of preconceptional FA and MV use

On the baseline and follow-up questionnaires, women were asked, ‘Do you take vitamins on a regular basis - daily or almost every day?’ If the response was positive, the women were asked to specify which of the following vitamins or minerals they were taking regularly: ‘MVs, vitamin A, beta-carotene, vitamin B, vitamin C, vitamin D, vitamin E, FA, calcium, magnesium, selenium and other’. Participants who reported ‘MV’ or listed a specific brand of MV in the ‘other’ section were classified as ‘MV users’. Similarly, participants who reported ‘FA’ or reported ‘folate’ ‘folacin’ or ‘FA’ in the ‘other’ section were classified as ‘FA users’. The baseline questionnaire also collected information on the duration of supplement use in the categories of <1 year, 1–5 years, >5 years and ‘do not know’.

Most MVs marketed in Denmark contain 400 μg of FA, especially those intended for the use during pregnancy. In addition, most women wrote the name of their MV product in the questionnaire, revealing if the MV included FA. Therefore, we created a single binary exposure variable defined as ‘FA supplementation’, which was set to one for women who were FA users, MV users or both. For women who used single vitamin or mineral supplements other than FA and women who did not take any dietary supplements, the exposure variable ‘FA supplementation’ was set to zero and was defined as ‘non-use’.

Assessment of pregnancies and cycles at risk

The main outcome of interest was the first reported pregnancy during the follow-up period, regardless of pregnancy outcome. The follow-up questionnaires included questions on the date of LMP, current pregnancy status and other pregnancy outcomes since the date of the last completed questionnaire, including miscarriage, induced abortion or ectopic pregnancy. Total number of cycles at risk was calculated as the following: (days of trying to conceive at study entry/cycle length)+[(LMP date from most recent follow-up questionnaire–date of baseline questionnaire completion)/usual cycle length)+1].18 We added one cycle to account for the average woman being at mid-cycle when she filled out the baseline questionnaire. The observed cycles at risk were defined as those contributed after study entry. For example, if a woman had been trying to conceive for five cycles before entering the study and then reported a pregnancy after 10 cycles of attempt time, she would contribute only five cycles.24 Participants who were lost to follow-up (n=337, 8.7%), changed their intention to become pregnant or actively resigned from the study (n=180, 4.6%) or did not conceive after 12 cycles (n=437, 11.2%) were censored at their last date of response. Participants who reported the use of fertility treatment (n=274, 7.0%) were censored at the date of reporting fertility treatment (Figure 1).

Assessment of covariates

Weight, height, physical activity and smoking history were reported at baseline, allowing the calculation of body mass index, total metabolic equivalents and pack-years of smoking. Total metabolic equivalent was estimated by summing up the metabolic equivalents from moderate physical activity (hours per week multiplied by 3.5) and vigorous physical activity (hours per week multiplied by 7.0).25, 26 We obtained data on other covariates, including age, level of education, history of spontaneous abortion, parity, timing and frequency of intercourse, alcohol consumption, attending the national screening programme for cervical cancer (pap smear) during the last 3 years, menstrual cycle regularity and cycle length and most recent method of contraception.

Data analysis

At baseline, 127 (3.3%) women did not answer the initial vitamin question. The amount of missing data for covariates ranged between 0.1% (body mass index) and 7.8% (alcohol intake). On the basis of all the information collected, including outcome variables, we used multiple imputation methods to impute missing exposure and covariate values.27, 28

We examined the association between FA supplementation (obtained either through single FA tablets or MV) and fecundability by calculating fecundability ratios (FRs) and 95% confidence intervals (CIs) using a proportional probabilities regression model.29 For the purpose of a sub-analysis, we also created three mutually exclusive categories of vitamin supplement use: FA and MV, MV exclusively and FA exclusively. The FR represents the cycle-specific probability of conception among exposed women divided by that among unexposed women. A FR above one indicates enhanced fecundability among FA supplement users relative to non-users. We also assessed the cumulative probability of pregnancy among FA supplement users and non-users across the 12-month follow-up period, using Kaplan–Meier curves.

In multivariate analyses (including Kaplan–Meier curves), we adjusted for potential confounders selected on the basis of the literature and clinical relevance. After restricting the analysis to FA supplement users, who were not using any other vitamins or minerals and who had been trying to conceive for 0–3 months at study entry (n=2289), we evaluated the extent to which the FR differed between FA supplementation for less than 1 year vs 1 year or more.

Because cycle regularity and cycle length may mediate the relation between FA supplementation and fecundability, we stratified the data by cycle regularity (regular and irregular) and cycle length (short (<27 days), medium (27–29 days) and long (30 days)). Because younger and parous women may have increased fecundability regardless of vitamin supplement use, we also stratified by age at study entry (18–30 and 31–40 years) and by parity (parous and nulliparous).

Results

Overall, 2560 respondents (65.7%) used FA supplements, obtained either through single FA tablets or MV, 62 (1.6%) used single vitamins or minerals other than FA and 1273 (32.7%) did not use any dietary supplements (Table 1). FA supplement use was associated with higher level of education, having at least one pap smear during the last 3 years, timing of intercourse and using barrier methods as the last method of contraception.

Table 1 Baseline characteristics of 3895 women by supplement use at baseline

Among the 3895 study participants, 2667 achieved a pregnancy within 12 cycles of follow-up, resulting in a crude cumulative probability of conception of 69%. This crude figure does not adjust for the fact that some women stopped trying to conceive and not all women remained under follow-up for the entire 12 cycles. Using life-table methods to handle this issue including delayed entry, the estimated probability of becoming pregnant within 12 cycles was 83%. Women lost to follow-up were less likely to use FA supplements (49% compared with 67% among women with complete follow-up). However, baseline characteristics of women who were lost to follow-up were similar to women with complete follow-up (data not shown).

FA supplementation and fecundability

After adjustment for potential confounders, FA supplementation was associated with increased fecundability (FR=1.15 (95% CI=1.06–1.25)) compared with non-use. Use of FA and MV, MV exclusively and FA exclusively showed similar associations, with adjusted FR of 1.12 (95% CI=1.03–1.23), 1.20 (95% CI=1.08–1.32) and 1.15 (95% CI=1.00–1.31), respectively, compared with non-use (Table 2). Among the 2289 women who had tried to conceive for 0–3 months at study entry, the adjusted FR for FA supplementation for less than 1 year was 1.15 (95% CI=1.03–1.28) compared with non-use. The corresponding FR was 1.04 (95% CI=0.92–1.19) for FA supplementation for more than 1 year compared with non-use.

Table 2 Fecundability by supplement use among 3895 women

Stratified analysis

After stratifying the data by menstrual cycle regularity and cycle length, the adjusted FRs for FA supplementation relative to non-use were 1.35 (95% CI=1.12–1.65) for women with irregular periods and 1.11 (95% CI: 1.01–1.22) for women with regular periods. The FRs were 1.36 (95% CI=0.95–1.95) for women with short cycles (<27 days), 1.10 (95% CI: 0.98–1.22) for women with medium cycle length (27–29 days) and 1.24 (95% CI=1.10–1.41) for women with long cycles (30 days). We found little effect of age or parity on the association between FA or MV use and fecundability. The adjusted FRs were 1.18 (95% CI=1.07–1.30) and 1.09 (95% CI=0.94–1.27) for women aged 18–30 years and 31–40 years, respectively, and 1.14 (95% CI=1.00–1.30) and 1.16 (95% CI=1.05–1.29) for parous women and nulliparous women, respectively (Table 3).

Table 3 Fecundability by FA supplement use stratified by selected factors (N=3895)

The adjusted Kaplan–Meier curve (Figure 2) shows that the 25th, 50th and 75th percentiles for the cumulative probability of conceiving were 2, 4 and 8 cycles, respectively, among FA supplement users and 2, 4 and 9 cycles, respectively, among non-users. These curves indicate that the association between FA supplement use and fecundability is relatively constant in our cohort across the 12 cycles of attempted pregnancy.

Figure 2
figure2

Kaplan–Meier, pregnancy probability curves by FA supplement use (N=3895). The curves are adjusted for age at baseline, vocational training, cycle regularity, parity, previous spontaneous abortion, pap smear, physical activity level, pack-years of smoking, alcohol intake, timing and frequency of intercourse, BMI, and last method of contraception used.

Discussion

In this prospective cohort study of Danish pregnancy planners, we found higher fecundability among users of FA supplements. Our findings agree with previous randomised trials reporting higher pregnancy rates among women who were taking MV supplements including 800 μg FA19 or 400 μg FA.15 We found no appreciable differences in FR among subgroups of FA or MV use.

Some selection bias could occur if vitamin supplement use is related to underlying fertility. Our study population consists of women planning a pregnancy, who may be less fertile than women experiencing unplanned pregnancies. In addition, women planning a pregnancy may be more aware of FA recommendations. These factors could have led us to underestimate the association between FA supplementation and fecundability. To address these issues, we excluded women who had tried to conceive for more than 6 cycles at study entry. Although there was a higher prevalence of FA supplement use among study participants who completed the study compared with those lost to follow-up, we found no major differences in other baseline characteristics between the two groups. Thus, it seems unlikely that this difference would cause bias.

Some participants may have reported being ‘FA users’ simply because they were asked or were planning to begin supplementation within a short time. This may have caused some misclassification. However, systematic bias in reporting vitamin supplement use seems unlikely because participants reported supplement use at baseline, before the occurrence of pregnancy. As we collected pregnancy status bimonthly, some misclassification of the outcome also may have occurred, but it is unlikely to be related to vitamin supplement use. Therefore, any misclassification errors in assessing supplement use and pregnancy status should bias our results towards the null.

Previously identified predictors of FA or MV use indicate various demographic, lifestyle and behavioural differences between users and non-users, for example, users are less likely to smoke and to consume alcohol.30, 31 Such health behaviours also may be related to fecundability and thus may confound the estimates. In the proportional probabilities regression model, we adjusted for several lifestyle factors, but some residual confounding remains possible because of roughly categorised variables in the questionnaires. Dietary factors may be a source of unmeasured confounding. However, the bioavailability of FA in supplements is generally higher than that of dietary folate,32, 33, 34 as synthetic FA is more stable and absorbable.35 Thus, it seems unlikely that a dietary factor would meaningfully confound the effect of FA supplementation on fecundability.

The study population comprised self-selected volunteers enroled via the Internet. Because all our comparisons were made within the population of our study participants, and because women who volunteered for the study did so before the occurrence of the outcome (pregnancy), the internal validity of the study should not be affected by the differences between study participants and the general population.36

In a randomised trial of 7905 women enroled in the Hungarian Family Planning Program, Czeizel et al.19 reported higher conception rates (64.6%) among women taking MV supplements including 800 μg FA than among women taking placebo-like trace elements (62.4%; odds ratio=1.10, 95% CI=1.00–1.21) during a 14-month follow-up period. In a trial of 30 women, who had tried unsuccessfully to conceive for 6–36 months, Westphal et al.15 also demonstrated increased pregnancy rates among women taking a MV supplement including 400 μg FA for 3 months, compared with women taking placebo. In our study, the associations between FA supplementation and fecundability were stronger among women with irregular menstrual cycles and among women with both short (<27 days) and long (30 days) cycle length. This suggests that the biological effect of FA on fecundability may be mediated in part by menstrual cycle hormones. FA supplementation could influence fecundability by several different mechanisms, such as alterations in DNA biosynthesis, multiple methylation reactions and accumulation of homocysteine. However, our data did not include biological specimens to investigate the biological mechanisms of our findings.

Although the exact duration of preconceptional FA supplementation was not assessed in this study, we found no evidence of increased fecundability among women using FA supplements for 1 year or more compared with those using FA for less than 1 year. A previous study showed an increase in plasma folate levels after 3 weeks among folate-depleted women receiving 300 μg of dietary folate per day,37 suggesting that folate deficiency is remedied quite quickly after supplementation. Another study found a significant increase in red-cell folate concentrations after 3 months of supplementation with 400 μg FA per day.32 Thus, it seems plausible that the biological effect of FA supplementation on fecundability may occur within a short time after the onset of supplementation, emphasising the importance of daily FA supplementation and indicating that longer preconceptional supplement use may not contribute to increased fecundability. As data on the exact dose of FA ingested were not collected in this study, an in depth evaluation of a potential dose–response relation between FA supplementation and fecundability was not possible.

Conclusion

Our findings suggest that preconceptional FA supplementation was associated with increased fecundability, and this association appeared to be stronger among women with irregular cycles and among women with either short or long cycle length. Longer duration of FA supplementation (one year or more) did not increase fecundability.

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Acknowledgements

We are grateful to Tina Christensen for her support with data collection and media contacts. The study was supported by the US National Institute of Child Health and Human Development (R21-050264) and the Danish Medical Research Council (271-07-0338). The funding sources had no influence on the study or the manuscript.

This study was supported by the National Institute of Child Health and Human Development (R21-050264) and the Danish Medical Research Council (271-07-0338). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Cueto, H., Riis, A., Hatch, E. et al. Folic acid supplementation and fecundability: a Danish prospective cohort study. Eur J Clin Nutr 70, 66–71 (2016). https://doi.org/10.1038/ejcn.2015.94

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