Abstract
STUDY QUESTION
Is self-reported use of omega-3 fatty acid supplements associated with fecundability, the probability of natural conception, in a given menstrual cycle?
SUMMARY ANSWER
Prospectively recorded omega-3 supplement use was associated with an increased probability of conceiving.
WHAT IS KNOWN ALREADY
In infertile women, omega-3 fatty acid intake has been associated with increased probability of pregnancy following IVF. In natural fertility, studies are conflicting, and no study of natural fertility has evaluated omega-3 fatty acid supplementation and fecundity.
STUDY DESIGN, SIZE, DURATION
Secondary data analysis of 900 women contributing 2510 cycles in Time to Conceive (TTC), a prospective, time to pregnancy cohort study from 2008 to December 2015.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women aged 30–44 years, trying to conceive <3 months, without history of infertility were followed using standardized pregnancy testing. While attempting to conceive, women daily recorded menstrual cycle events and supplement and medication intake using the Cerner Multum Drug Database. Supplements and vitamins containing omega-3 were identified. Omega-3 use, defined as use in at least 20% of days in a given menstrual cycle, in each pregnancy attempt cycle was determined. A discrete-time Cox proportional hazards model was used to calculate the fecundability ratio.
MAIN RESULTS AND THE ROLE OF CHANCE
Women taking omega-3 supplementation were more likely to be younger, thinner, nulligravid, white and to take vitamin D, prenatal and multivitamins compared to women not taking omega-3s. After adjusting for age, obesity, race, previous pregnancy, vitamin D and prenatal and multivitamin use, women taking omega-3 supplements had 1.51 (95% CI 1.12, 2.04) times the probability of conceiving compared to women not taking omega-3s.
LIMITATIONS, REASONS FOR CAUTION
Our study was not a randomized controlled trial. The women who used omega-3 supplements may represent a more health-conscious population. We sought to address this by adjusting for multiple factors in our model. Additionally, the omega-3 fatty acid supplements that TTC participants used included multiple types and brands with varying dosages of omega-3 fatty acids. Women reported the type of supplement they were taking but not the concentration of omega-3s in that supplement. It is therefore not possible to compare dosing or a dose–response relationship in our study.
WIDER IMPLICATIONS OF THE FINDINGS
Omega-3 supplementation may present a feasible and inexpensive modifiable factor to improve fertility. Randomized controlled trials are needed to further investigate the benefits of omega-3 supplementation for women trying to conceive naturally.
STUDY FUNDING/COMPETING INTERESTS
This study was supported by the Division of Reproductive Endocrinology and Infertility at the University of North Carolina at Chapel Hill, the NIH/NICHD (R21 HD060229-01 and R01 HD067683-01), and in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01ES103333). The authors declare that there is no conflict of interest.
TRIAL REGISTRATION NUMBER
N/A.
Keywords: omega-3 fatty acids, supplementation, polyunsaturated fatty acids, natural fertility, fecundability
Introduction
According to the Centers for Disease Control and Prevention (CDC), 10–16% of couples have difficulty conceiving, and this may be greater in women who are pursuing their first pregnancy and with advancing age (Chandra et al., 2013; Steiner and Jukic, 2016). Subfertility and infertility are associated with significant psychosocial ramifications including but not limited to increased risk of anxiety and depression (Stanhiser and Steiner, 2018). Optimizing natural fertility is therefore ideal, however, there are currently few known modifiable factors to improve the probability of natural conception in a given menstrual cycle (American Society for Reproductive Medicine, 2017).
Omega fatty acids, polyunsaturated fatty acids (PUFA) that are essential to human physiology, must be consumed from the diet (Simopoulos, 2008). Multiple studies have found that a diet higher in omega-3 fatty acids is associated with improved health and reduced risk of chronic diseases (Simopoulos, 2008, 2016; Russo, 2009; Gomez Candela et al., 2011; Calder, 2013). Omega fatty acids may also play important roles in reproduction (Wathes et al., 2007). Omega fatty acids are sources of cholesterol, the main precursor for all steroid hormones, and are involved in cellular energy provision, as well (Wathes et al., 2007; Sturmey et al., 2009). In animal models, omega-3 supplementation has been shown to alter prostaglandin biosynthetic pathways, and may impact steroidogenesis, folliculogenesis and oocyte maturation, ovulation, fallopian tube motility, implantation and even prolong the female reproductive lifespan (Norwitz et al., 2001; Clark and Myatt, 2009; Downs et al., 2009; Sturmey et al., 2009; Nehra et al., 2012; Ponter et al., 2012; Meher et al., 2013; Elis et al., 2016; Leghi and Muhlhausler, 2016; Gokuldas et al., 2018; Rodríguez et al., 2018). However, little is known about the effects of omega-3 supplementation on human fecundity.
Currently, there is evidence limited to the evaluation of dietary fat intake and omega-3 fatty acid serum concentration in natural fertility, with conflicting findings (Chavarro et al., 2007; Mumford et al., 2016; Wise et al., 2018, 2020). No study on natural fertility has evaluated omega-3 fatty acid supplementation and fecundity. While studies in natural fertility are limited, studies in the infertile population consistently report favorable associations between omega-3 fatty acid dietary intake and supplementation, and reproductive endpoints in women undergoing ART, particularly IVF (Vujkovic et al., 2010; Moran et al., 2016; Nouri et al., 2017).
Given the dearth of literature on the impact of omega-3 fatty acids on natural fertility, and the promising findings in the infertile population, we sought to determine the association between omega-3 fatty acid supplementation and fecundability in women without a history of infertility. Our hypothesis was that omega-3 supplementation would increase the probability of a woman conceiving.
Materials and methods
Study population
This is a secondary data analysis of Time to Conceive (TTC), a prospective, time-to-pregnancy cohort study, which was conducted from 2008 to December 2015. Both the original TTC protocol and this secondary analysis were approved by the institutional review board of the University of North Carolina. TTC enrolled 1036 women between the ages of 30 and 44 who had been trying to conceive for <3 months and had no history of infertility or related conditions (Steiner et al., 2017). All participants provided written informed consent. At enrollment, participants completed a questionnaire on medical and reproductive history, lifestyle habits including but not limited to frequency of intercourse, caffeine and alcohol intake, and medication use. While attempting to conceive, women completed daily diaries for up to 4 months that solicited information on intercourse and menstrual cycle events. In addition, women daily reported the generic or brand name of their vitamin, supplement and medication intake using the Cerner Multum Drug Database (Cerner Multum, 2008) which categorizes therapeutic substances into classes based on their active ingredients. Women also completed questionnaires monthly that inquired about exercise. Participants were given pregnancy tests and standardized pregnancy testing instructions. Women who reported a positive pregnancy test were offered a first-trimester ultrasound.
Omega-3 fatty acid supplement use
Using the data recorded from the Cerner Multum Drug Database, supplements and vitamins containing omega-3 fatty acids (e.g. docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), prenatal vitamin formulations including omega-3 fatty acids, flaxseed oil and fish oil) were identified independently by two study authors (A.M.J. and D.R.M.; Cerner Multum, 2008). Omega-6 supplements (walnut oil, rosehip oil), and Coenzyme Q10 were also identified, but they were very rarely consumed in the population so were not considered further. The number of days on which a woman reported taking a supplement containing omega-3 fatty acids was calculated for a given menstrual cycle. This number of days was then divided by the number of days during that menstrual cycle that she recorded data in the daily diary to estimate the percentage of the cycle with omega-3 fatty acid supplement use. Cycle-specific prenatal and multivitamin usage was calculated in similar fashion. Because women completed daily diaries in TTC for only the first 4 months of their participation in the study by design, this analysis is limited to the pregnancy attempt time that was recorded during daily diary participation. Women or menstrual cycles without daily diary data, or menstrual cycles occurring after daily diary participation per the TTC protocol, were excluded from the analysis (Fig. 1). Additional exclusion criteria included women who withdrew from participating in the study, and menstrual cycles following the initiation of fertility treatment. This left 900 women (2510 cycles) in the analysis, including times from Cycle 1 to Cycle 7 of the attempt.
Figure 1.
Flow of study participants in this secondary data analysis of Time to Conceive cohort study data.
Pregnancy attempt time
A woman’s current estimated pregnancy attempt cycle was determined from the time a woman started trying to conceive, not from the time of enrollment. Attempt cycle at enrollment was defined by the pregnancy attempt cycle (usually Cycle 1, 2 or 3) in which the woman began participation in TTC. Women were censored at the time they withdrew, started fertility medications, completed their time of daily diary recording (about 4 months) or were lost to follow-up. Thus, cycles from enrollment to the end of daily diary participation (censoring) or pregnancy detection were included in the analysis. Conception was defined as a positive home pregnancy test based on kits that had been provided to participants.
Statistical analysis
Univariable statistics were used to describe the demographic characteristics of the total cohort using means and frequencies. We compared women who did and did not take omega-3 supplements in the first cycle of enrollment using Student’s t-tests and chi-squared tests, where appropriate.
We used a discrete-time Cox proportional hazards model to estimate the fecundability ratio (FR). The FR is the relative probability of conception in a given cycle for the exposed group relative to the reference group or for one level of a continuous exposure compared to a lower level. In such models, an FR of greater than 1 suggests increased fecundability in the exposed group.
To determine the shape of the association between omega-3 supplementation and fecundability, we evaluated several parameterizations of omega-3 supplement use using the discrete Cox model described above. Exposure variables considered in the models included linear, squared, cubed, deciles, quintiles, quartiles and tertiles. We used Akaike’s Information Criterion (AIC) to choose the best-fitting parameterization of omega-3 supplementation. Based on the AIC, a cutoff value of 20% was used to dichotomize omega-3 use in each cycle. Thus, cycles in which a woman consumed omega-3 supplements on 20% or more of the days in a given cycle, were considered omega-3 supplement-exposed cycles. Covariates found to be associated with omega supplement usage in bivariate analyses were added to the model. The final model included age (30–34, 35–37, 38–44 years), obesity (BMI ≥30.0 kg/m2), race (White, non-White), history of prior pregnancy and cycle-specific vitamin D intake as categorical variables. Vitamin D supplement use was categorized in quintiles. Most women taking omega-3 supplementation were also taking a prenatal vitamin or a multivitamin. While acknowledging the potential for significant collinearity, an additional model was created in which we controlled for prenatal and multivitamin intake. Based on the AIC, a cutoff value of 20% was used in the model to dichotomize prenatal vitamin and multivitamin use in each cycle. A sensitivity subgroup analysis limited to women taking either a prenatal or multivitamin was conducted. In this sensitivity analysis, both groups are taking either a prenatal or multivitamin, allowing us to estimate the independent effect of omega-3 supplement use. Further modeling was performed in a cross-classified group analysis to compare women not taking an omega-3 supplement or a multivitamin/prenatal vitamin (MTV/PNV) to women taking an MTV/PNV with no omega-3 use and women taking both an MTV/PNV and an omega-3 supplement. An additional sensitivity analysis limiting the analysis to cycles in which at least 20 days were recorded in the daily diary was performed. Finally, a further sensitivity analysis was performed for unmeasured confounding.
As a secondary outcome, we investigated the correlation between the intake of omega-3 fatty acid supplements and the measured omega-3 fatty acid serum concentrations from our previous nested case-control study of 200 women randomly selected from TTC (Stanhiser et al., 2020). In that study, nonfasting serum omega-3 PUFA concentrations measured in peak area ratio using liquid chromatography–mass spectrometry were assessed in the early follicular phase of the first menstrual cycle following enrollment. The omega-3 fatty acid serum concentrations of alpha-linolenic acid (ALA), EPA and DHA were compared to the percentage intake of omega-3 fatty acid supplements in the first cycle of enrollment using Pearson’s correlation and variance explained. Student’s t-test was used to compare the mean concentration of ALA, EPA and DHA between women taking and not taking omega-3 supplements.
P < 0.05 was considered statistically significant. All statistical analyses were performed using Stata 15.0.
Results
Study flow is presented in Fig. 1. A total of 1036 women enrolled in TTC, contributing 4758 cycles. Of these, 2248 cycles (from 136 women) that occurred after daily diary recording concluded were missing daily diary data, or otherwise met exclusion criteria were excluded from analysis. Therefore, a total of 2510 cycles (from 900 women) were analyzed. Eighty-eight percent of cycles had daily data recorded for at least 20 days. Most women reported every day of their cycle, with a mean of 27 days of daily-reported data per cycle. Of recorded days, <0.5% of them were missing any daily diary variable data. Participant characteristics are presented in Table I. Mean age was 33.76 ± 3.13 years, and mean BMI was 24.72 ± 5.42. The majority of women were white, educated and married, had regular periods and no history of smoking. Nearly half of the women had been pregnant before.
Table I.
Demographic characteristics of all study participants (N = 900).
Characteristic | Mean ± SD or n (%) |
---|---|
Age (years) | 33.8 ± 3.1 |
30–34 | 625 (69.4%) |
35–37 | 169 (18.8%) |
38–44 | 106 (11.8%) |
BMI (kg/m2) | 24.7 ± 5.4 |
AMH (ng/ml) | 3.9 ± 3.6 |
Previous pregnancy | 447 (49.7%) |
Regular periods | 779 (86.6%) |
Menstrual cycle length (days) | 30.6 ± 8.2 |
Race | |
White | 696 (77.3%) |
Non-White | 204 (22.7%) |
Education level | |
College or less | 241 (26.8%) |
Some graduate school or more | 659 (73.2%) |
Married | 833 (92.6%) |
Smoking status | |
Never | 692 (76.9%) |
Past | 196 (21.8%) |
Current | 12 (1.3%) |
Hormonal contraceptive use in previous year | 415 (46.1%) |
Intercourse frequency per week (days)* | 2.33 ± 1.5 |
Intercourse frequency during fertile window (percentage of fertile days)* | 40.4% ± 25.8% |
Hours of vigorous exercise in the past* month | |
0 h | 74 (11.5%) |
<1 h | 123 (19.2%) |
1–3 h | 261 (40.7%) |
4–7 h | 143 (22.3%) |
>7 h | 38 (5.9%) |
Unsure | 2 (0.3%) |
Number of alcoholic beverages per month* | 7.4 ± 9.4 |
Number of caffeinated beverages per day* | 1.2 ± 0.9 |
Coenzyme Q10 use* | 2 (0.2%) |
Vitamin D intake (IU)* | 234.6 ± 2620.4 |
Prenatal vitamin use* | 332 (36.9%) |
Multivitamin use* | 112 (12.4%) |
Exercise data were missing for 259 women.
As reported in the first cycle of enrollment.
AMH, anti-Müllerian hormone.
Comparison of participant characteristics between women taking and not taking omega-3 supplements in their first study cycle of enrollment are presented in Table II. Women taking omega-3 supplements were more likely to be younger, thinner, nulligravid, white and to take vitamin D supplements, prenatal vitamins and multivitamins compared to women not taking omega-3 supplementation. Of 113 women taking omega-3 supplements, 111 also took a prenatal vitamin or a multivitamin (98.23%). There were many women taking prenatal vitamins or multivitamins who were not taking omega-3 supplements (N = 333). There was no difference in intercourse frequency or timing between groups. We observed women for 3–4 cycles and patterns of supplement use did not significantly change in that time period. Frequency of intake in the first cycle was 12% and in the last cycle 11% (P = 0.5689). In cycles reporting omega-3 use, distribution of the percentage of days per menstrual cycle omega-3 supplements were taken is presented in Fig. 2. For 82.7% of the cycles in omega-3 supplement users, omega-3 supplements were taken in at least 50% of the days in that cycle. This means that for omega-3 supplement users in our study, omega-3 supplements were taken for at least half of the cycle in over 80% of cycles. Women taking omega-3 supplements were significantly more likely to conceive (N = 96 out of 113, or 84.96%) compared to women not taking omega-3 supplements (N = 409 out of 787, or 51.97%), P < 0.001.
Table II.
Bivariate analyses of participants taking and not taking omega-3 supplements in their first cycle of enrollment in the time to conceive (TCC) study.
No omega-3 supplements | Omega-3 supplements | |
---|---|---|
(N = 787) | (N = 113) | |
Mean ± SD or N (%) | ||
Age (years) | 33.8 ± 0.1 | 33.2 ± 0.2 |
30–34 | 536 (68.11%) | 89 (78.76%) |
35–37 | 151 (19.19%) | 18 (15.93%) |
38–44 | 100 (12.71%) | 6 (5.31%) |
BMI (kg/m2) | 24.9 ± 0.2 | 23.1 ± 0.4 |
AMH (ng/ml) | 3.9 ± 0.1 | 4.3 ± 0.4 |
Previous pregnancy | 402 (51.1%) | 45 (39.8%) |
Regular periods | 681 (86.5%) | 98 (86.7%) |
Menstrual cycle length (days) | 32.5 ± 0.4 | 32.7 ± 0.9 |
Race | ||
White | 594 (75.5%) | 102 (90.3%) |
Non-White | 193 (24.5%) | 11 (9.7%) |
Education level | ||
College or less | 220 (28.0%) | 21 (18.6%) |
Some graduate school or more | 567 (72.1%) | 92 (81.4%) |
Married | 726 (92.3%) | 107 (94.7%) |
Smoking status | ||
Never | 602 (76.5%) | 90 (79.7%) |
Past | 175 (22.2%) | 21 (18.6%) |
Current | 10 (1.3%) | 2 (1.8%) |
Intercourse frequency per week (days) | 2.3 ± 0.1 | 2.4 ± 0.2 |
Number of alcoholic beverages per month | 7.5 ± 0.4 | 6.6 ± 0.8 |
Number of caffeinated beverages per day | 1.2 ± 0.0 | 1.09 ± 0.1 |
Intercourse frequency during fertile window (percentage of fertile days)* | 40.5% ± 1.1% | 39.4% ± 2.9% |
Hours of vigorous exercise in the past month* | ||
0 h | 71 (12.6%) | 3 (3.9%) |
<1 h | 112 (19.9%) | 11 (14.3%) |
1–3 h | 226 (40.1%) | 35 (45.5%) |
4–7 h | 122 (21.6%) | 21 (27.3%) |
>7 h | 31 (5.5%) | 7 (9.7%) |
Unsure | 2 (0.4%) | 0 (0.0%) |
Number of alcoholic beverages per month* | 7.5 ± 0.4 | 6.6 ± 0.8 |
Number of caffeinated beverages per day* | 1.2 ± 0.0 | 1.1 ± 0.1 |
Vitamin D intake (IU)* | 159.3 ± 75.2 | 759.2 ± 456.4 |
Prenatal vitamin use* | 244 (31.0%) | 88 (77.9%) |
Multivitamin use* | 89 (11.3%) | 23 (20.4%) |
Exercise data were missing for 259 women.
As reported in the first cycle of enrollment.
AMH, anti- Müllerian hormone.
Figure 2.
Distribution of the percentage of days per menstrual cycle on which omega-3 supplements were taken in 286 cycles.
The association between omega-3 supplementation and the probability of conceiving is shown in Table III. Women taking omega-3 supplements had 2.20 (95% CI 1.68, 2.88) times the probability of conceiving in a given menstrual cycle compared to women not taking omega-3 supplements. After adjusting for age, obesity, race and vitamin D intake, women taking omega-3 supplements had 2.04 (95% CI 1.53, 2.71) times the probability of conceiving in a given menstrual cycle, compared to women not taking omega-3 supplements. Further adjusting the model to also include history of previous pregnancy, women taking omega-3 supplements had 2.12 (95% CI 1.59, 2.82) times the probability of conceiving in a given menstrual cycle, compared to women not taking omega-3 supplements. While acknowledging the potential for significant collinearity with 98.23% of women taking omega-3 supplements also taking a prenatal or multivitamin, prenatal and multivitamin use were incorporated into an additional model, which changed the effect estimates by 30% (FR 1.45 (95% CI 1.07, 1.93) adjusting for age, obesity, race, vitamin D, prenatal and multivitamin use; FR 1.51 (95% CI 1.12, 2.04) adjusting for age, obesity, race, previous pregnancy, vitamin D, prenatal and multivitamin use).
Table III.
Association between omega-3 supplementation and probability of conceiving.
Omega-3 supplement use | ||
---|---|---|
Main analysis (N = 900) | ||
Unadjusted fecundability ratio | 2.20 (95% CI 1.68, 2.88) | |
Adjusted fecundability ratio | 2.04 (95% CI 1.53, 2.71)* | 2.12 (95% CI 1.59, 2.82)** |
Adjusted fecundability ratio further adjusting for PNV and MTV use | 1.45 (95% CI 1.07, 1.93)* | 1.51 (95% CI 1.12, 2.04)** |
Sensitivity analysis limited to women taking PNV or MTV (N = 486) | ||
Unadjusted fecundability ratio | 1.34 (95% CI 0.97, 1.85) | |
Adjusted fecundability ratio | 1.30 (95% CI 0.93, 1.81)* | 1.32 (95% CI 0.94, 1.84)** |
Adjusted for age, obesity, race and vitamin D intake.
Adjusted for age, obesity, race, vitamin D intake and previous pregnancy.
MTV, multivitamin; PNV, prenatal vitamin.
A sensitivity analysis was performed limited to women taking a prenatal or multivitamin (N = 486), in which women taking omega-3 supplements had 1.34 (95% CI 0.97, 1.84) times the probability of conceiving in a given menstrual cycle compared to women not taking omega-3 supplements. After adjusting for age, obesity, race and vitamin D intake, women taking omega-3 supplements had 1.30 (95% CI 0.93, 1.81) times the probability of conceiving in a given menstrual cycle, compared to women not taking omega-3 supplements. Further adjusting the model to also include history of previous pregnancy, women taking omega-3 supplements had 1.32 (95% CI 0.94, 1.84) times the probability of conceiving in a given menstrual cycle, compared to women not taking omega-3 supplements.
Finally, in a cross-classified group analysis, compared to women not taking an omega-3 supplement or an MTV/PNV (N = 454), in a given cycle of trying to conceive: women taking an MTV/PNV with no omega-3 use (N = 333) were 3.67 times more likely to conceive (FR 3.67, 95% CI 2.92, 4.62), while women taking both an omega-3 supplement and an MTV/PNV (111) were 4.35 times more likely to conceive (FR 4.35, 95% CI 3.18, 5.94). Please see Supplementary Table SI for these FRs, with models adjusting for age, obesity, race, vitamin D intake and previous pregnancy. Sensitivity analysis limiting the analysis to cycles in which at least 20 days were recorded in the daily diary was performed and the results did not change (data not shown).
Secondary outcome
ALA serum concentration was not correlated with omega-3 supplement use (r = -0.094 P = 0.186). EPA and DHA serum concentrations and omega-3 supplement use were weakly correlated (r = 0.280 P = 0.001; r = 0.2401 P = 0.007, respectively), signifying that 7.85% and 5.76% of the variance in EPA and DHA are explained or predicted by omega-3 supplement use.
Mean ALA serum concentration was not higher in women who took omega-3 supplements compared to women who did not (0.035 and 0.049, respectively, P = 0.121). Mean EPA and DHA serum concentrations were significantly higher in women who took omega-3 supplements compared to women who did not (EPA 0.00744 and 0.00439, respectively, P = 0.0001; DHA 0.032 and 0.023, respectively, P = 0.008).
Discussion
Omega-3 supplement use on at least 20% of menstrual cycle days was associated with about twice the probability of conception. While adjustment for most factors did not substantially alter this estimate, adjusting for prenatal or multivitamin use reduced the association to 1.5 times the probability of conception. In our sensitivity analysis limited to women taking a prenatal or multivitamin, women taking an omega-3 supplement had 1.3 times the probability of conception. To our knowledge, our study is the first to examine omega-3 supplement use and spontaneous conception in humans.
We found that omega-3 supplements may increase a woman’s fertility. While prior cohort studies have not examined supplementation, they have examined omega-3 dietary intake. Wise et al. (2018) evaluated two large cohorts, one North American and the other Danish, with potentially conflicting findings. In the North American PRESTO (Pregnancy Study Online) cohort of 1290 women, increased omega-3 fatty acid dietary intake was associated with higher fecundability with FR 1.4 (95% CI 1.13, 1.73), similar to the FR we observe in our study. In the Snart Foraeldre Denmark cohort of 1126 women, no association was found (Wise et al., 2018). The differences in findings may be due to demographic differences in the study populations. The Snart Foraeldre Denmark cohort had higher dietary intake of omega-3 fatty acids, and low dietary intake of omega-3 fatty acids was uncommon, potentially explaining the lack of association due to a threshold effect. However, in a later study of these two populations (PRESTO North American cohort of 5127 women; Snart Foraeldre Denmark cohort of 2709 women), intake of seafood was not appreciably associated with fecundability in either cohort (Wise et al., 2020). Gaskins et al. (2018) in the Longitudinal Investigation of Fertility and the Environment (LIFE) study evaluated fish intake (the main source of marine omega-3 fatty acids in the US population) and time to pregnancy and found that prospective seafood intake in cycles was associated with fecundability after multivariable adjustment, with FR 1.44 (95% CI 1.04, 2.01), similar to our observed FR; however, baseline seafood intake was not.
In a previous study, we sought to determine if serum omega-3 PUFA concentrations were associated with the probability of conceiving naturally (Stanhiser et al., 2020). We assessed nonfasting serum omega-3 PUFA concentration in the early follicular phase of the first menstrual cycle following enrollment from 200 women randomly selected from TTC in a nested case-control study. We found no strong association between serum concentrations of omega-3 fatty acids and the probability of conceiving naturally within 12 cycles of attempt. Mumford et al. (2018) similarly observed in a prospective cohort study of 1228 women that baseline omega-3 fatty acid serum concentrations were not associated with fecundability. Our findings in our previous study that baseline omega-3 fatty acid concentrations were not associated with fecundability, and in our current study that prospective omega-3 fatty acid supplementation may improve fecundability, are consistent with the findings of Gaskins et al. (2018), above.
In our current study, omega-3 supplement use weakly correlated with the measured serum concentrations of EPA and DHA from our previous study. Our disparate findings between these two studies within the TTC cohort and the observed weak correlation between serum concentrations and supplement intake may be due to several considerations. First, while previous studies suggest that blood levels of fatty acids can be a reasonably good biomarker of habitual dietary fat intake, less is known about the accuracy of biomarkers for omega-3 supplementation (Maki, 2018). Studies now show that the bioavailability of EPA and DHA from omega-3 supplements is highly dependent on their consumption with a fat-containing meal to stimulate the release of bile salts into the small intestine (Qin et al., 2017; Maki, 2018). Other studies have demonstrated that likely the strongest biomarker of long-term omega-3 fatty acid intake is their distribution in adipose tissue (Arab, 2003). Second, in our previous study, omega-3 fatty acid concentrations were derived from serum provided at baseline at a single timepoint in the first cycle of enrollment. As these were single assessments, there is also the possibility of a measurement error. Another consideration is that the concentrations detected may not be representative of all critical timepoints in the menstrual cycle or throughout each subsequent cycle of attempt to conceive. As the fatty acid concentrations were assessed at baseline, they reflect prior intake of omega-3 fatty acids and may not be fully representative of the prospective daily omega-3 supplement intake assessed in the current study. If supplement usage was several days before or after a woman’s serum collection (with omega-3 PUFA metabolism consisting of half-lives of 67 h for EPA and 20 h for DHA) or if her most recent supplement usage was not proximal in time to a meal containing sufficient fat, her intake would not be reflected in our analysis of her omega-3 serum concentrations. Finally, with an N = 200, our previous study was limited by sample size. If there is an association between serum omega-3 PUFA concentrations and fecundability, a significantly larger sample size than our previous study would very likely be needed to detect an association. In cases where serum omega-3 PUFA concentrations have been found to be associated with certain health outcomes, large meta-analyses were necessary to detect these results. For example, in a systematic review and meta-analysis of dietary intake (not supplementation) or blood levels of omega-3 PUFA and the risk of colorectal cancer, 20 prospective studies including 1 360 046 participants were combined to detect their results (Kim and Kim, 2020). In another meta-analysis of omega-3 PUFA biomarkers and coronary heart disease, 19 cohort studies including 45 637 participants were pooled in their data (Del Gobbo et al., 2016). Studies were included in this meta-analysis if fatty acids were measured in adipose tissue, given the stability of adipose measures compared to serum.
The mechanism of action by which omega-3s may impact human fertility is not clear. In the BioCycle prospective cohort study of 259 regularly menstruating women, Mumford et al. (2016) found that increased omega-3 fatty acid dietary intake was associated with a lower risk of anovulation. However, in the Nurses’ Health Study II (NHS-II) prospective cohort study of 18 555 women by Chavarro et al. (2007), no association between dietary omega-3 fatty acid intake and ovulatory function or ovulatory infertility was found. Further research is needed to first confirm our findings and then determine the mechanisms by which omega-3 fatty acids may impact natural fertility.
While studies in natural fertility have been previously limited to omega-3 fatty acid serum concentration and evaluation of dietary fat intake without data on omega-3 fatty acid supplementation, studies of both omega-3 fatty acid dietary intake and supplementation in infertile populations consistently report favorable associations with reproductive endpoints in ART. In a prospective, randomized trial including 100 women, Nouri et al. (2017) found that omega-3 supplementation improved embryo quality for women undergoing IVF, with relative risk (RR) 1.611 (95% CI 1.009, 2.597) compared to women not taking omega-3 supplementation. A preconception Mediterranean diet (rich in omega-3 fatty acids) was associated with increased probability of pregnancy following IVF with odds ratio (OR) 1.4 (95% CI 1.1, 1.9) in a prospective cohort study of 161 couples by Vujkovic et al. (2010). Moran et al. (2016) prospectively randomized 46 overweight and obese women to a preconception diet and physical activity intervention group and a control group, and found that increased omega polyunsaturated fatty acid intake was associated with a higher pregnancy rate in IVF with OR 1.27 (95% CI 1.01, 1.61). In the Environmental and Reproductive Health (EARTH) cohort, increased omega-3 fatty acid intake and serum omega-3 PUFA concentrations measured within the stimulation cycle were positively associated with the probability of pregnancy and live birth (Chiu et al., 2018). Specifically, after multivariable adjustment, the probability of clinical pregnancy increased by 8% (95% CI 1%, 16%) and the probability of live birth increased by 8% (95% CI 1%, 16%) for every 1% increase in serum long-chain omega-3 (EPA and DHA) levels. Intake of long-chain omega-3s was also associated with a higher probability of a live birth with RR 2.37 (95% CI 1.02, 5.51) (Chiu et al., 2018). These studies may be limited by sample size, and further investigation is needed to evaluate the impact of omega-3 fatty acids on reproductive endpoints for women with and without infertility.
Our study has several limitations. First, it is a secondary data analysis of TTC, and our analysis is limited to the pregnancy attempt time recorded during daily diary participation in the TTC protocol. Women completed daily diaries in TTC for only the first 4 months of their participation in the study by design, and therefore, each cycle included represents the four most fertile cycles within our study for each woman. While we see a benefit from omega-3 supplementation in these earlier cycles of attempt, it may not be present in later cycles. Of note, this limitation is due to how the TTC protocol was designed, and not due to lack of participation. Second, TTC is an older cohort (30–44 years of age), and therefore, our findings may not be generalizable to younger women. Third, supplements are not subject to the same strict efficacy and quality control requirements by the U.S. Food & Drug Association (FDA) compared to other conventional drug products (U.S. FDA Dietary Supplements, accessed 2019). Fourth, the omega-3 fatty acid supplements that the TTC participants used included multiple types and brands with varying dosages of omega-3 fatty acids. In our study, women reported the type of supplement they were taking (i.e. fish oil, EPA, DHA), but not the concentration of omega-3s in that supplement. While we have data on how often each woman took a supplement, and what she was taking, we do not know the amount of omega-3 fatty acid in each pill or capsule, and we do not know how many pills or capsules she took each time. It is therefore not possible to compare dosing or a dose–response relationship in our study. Fifth, we do not have supplement data on partners. However, we have partner information for several characteristics such as age, race, smoking status and BMI. Adjustment for these characteristics did not impact our results. Further, adjustment for these characteristics may partially adjust for any potential confounding from partner supplement use, as they are likely to be correlates of supplement use. Although couples may have similar diets, the conjecture that couples may also take the same supplements is not necessarily true. Many women in our study took omega-3 supplements through their prenatal vitamin, making it even less likely that the male partner took the same omega-3 fatty acid supplement. While several randomized controlled trials have found that male omega-3 supplement use may have a positive association with testicular function including improved total sperm count and progressive sperm motility, and decreased sperm DNA fragmentation, this does not necessitate an association between male omega-3 supplement use and fertility outcomes such as pregnancy and live birth, which, to our knowledge, have not been studied (Safarinejad, 2011; Martínez-Soto et al., 2016; González-Ravina et al., 2018; Jensen et al., 2020). The MOXI randomized clinical trial (Males, Antioxidants and Infertility Trial) found that male general supplement use did not impact semen parameters or improve pregnancy or live birth rate (Steiner et al., 2020).
A further limitation of our study is that it was not a randomized controlled trial. The women who used omega-3 supplements in our study may represent a more health-conscious population than women who were not using omega-3 supplements. We sought to address this by adjusting for age, obesity, previous pregnancy, Vitamin D, prenatal and multivitamin intake in our model. We further addressed this limitation in a sensitivity analysis limited to women taking a prenatal and multivitamin wherein women taking an omega-3 supplement had 1.3 times the probability of conception. Finally, in a cross-classified group analysis, compared to women not taking an omega-3 supplement or an MTV/PNV, women taking an MTV/PNV with no omega-3 use were 3.67 times more likely to, while women taking both an omega-3 supplement and an MTV/PNV were 4.35 times more likely to conceive. While we have seen this association and we attribute it to omega-3 use, certainly another reason we are seeing this could be due to synergy between omega-3 and prenatal/multivitamin use, or residual confounding. However, if it were synergy, we would expect that the analysis limited to prenatal/multivitamin users would show stronger effect estimates when compared with the estimates that include nonprenatal/multivitamin users, but this was not the case. The estimates were somewhat smaller in the group of prenatal/multivitamin users. Regarding residual confounding, consumption of dietary supplements is associated with more healthful lifestyle practices (Dickinson and MacKay, 2014). Therefore, we adjusted for multivitamin, prenatal vitamin and vitamin D usage in our analyses, and a positive association with omega-3 supplement use and fecundability remains. While we cannot rule out confounding by healthful lifestyle factors not captured by measured variables, omega-3 users would have to have different healthful lifestyle practices than other supplement users for this to be the case. In a sensitivity analysis, an unmeasured confounder could produce the association we saw in this study if it is highly prevalent in omega users (RR = 2.0–4.0) and has a moderate to strong association with high fecundability (1.80–4.0). For example, an unmeasured confounder that is highly prevalent in omega users (RR = 4.0) and with a moderate association with fecundability (RR = 1.80) could produce the association we saw. Or, a confounder that is moderately prevalent in omega users (RR = 2.0) but has a very strong association with fecundability (RR = 4.0) could also produce the association we saw in this paper. However, there are very few predictors of time to pregnancy and none of them are strong. Additionally, any unmeasured, unknown confounder would have to act independently of all the factors we controlled for (including prenatal, multivitamin and vitamin D use, demographics and other behaviors). While this is possible, we cannot hypothesize which healthful behaviors would be unique to omega-3 supplement users.
Our study has several strengths. First, this is the first study to analyze omega-3 supplementation in women attempting to conceive naturally. Second, TTC is a unique, prospective time-to-pregnancy study consisting of a large cohort of women. Participants were enrolled in the first 1–3 months of trying to conceive, before supplement-taking behaviors might have been influenced by concern about fertility. The study protocol was standardized for detection of the primary outcome measure, a positive pregnancy test. Third, omega-3 supplementation usage was recorded daily using a drug database.
Conclusions
Our data suggest omega-3 supplementation may increase the probability of a woman conceiving. Omega-3 supplementation may present a feasible and inexpensive modifiable factor to improve fertility. Additional cohort studies and ideally randomized controlled trials are needed to further investigate the benefits from omega-3 supplementation for women trying to conceive naturally.
Supplementary data
Supplementary data are available at Human Reproduction online.
Data availability
The data underlying this article were provided by Time to Conceive by permission. Data will be shared on request to the corresponding author with permission from Time to Conceive.
Supplementary Material
Acknowledgements
We appreciate Dr. Clarice Weinberg’s comments on an earlier draft of this manuscript.
Authors’ roles
J.S., MD: Participation in study design, execution, analysis, manuscript drafting and editing, and critical discussion. A.M.Z.J., PhD, MSPH: Participation in study design, analysis, manuscript drafting and editing, and critical discussion. D.R.M., PhD: Participation in study design, analysis, manuscript drafting and editing, and critical discussion. A.Z.S., MD, MPH: Participation in study design, execution, analysis, manuscript drafting and editing, and critical discussion.
Funding
This study was supported by the Division of Reproductive Endocrinology and Infertility at the University of North Carolina at Chapel Hill, the NIH/NICHD (R21 HD060229-01 and R01 HD067683-01), and in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01ES103333).
Conflict of interest
The authors declare that there is no conflict of interest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article were provided by Time to Conceive by permission. Data will be shared on request to the corresponding author with permission from Time to Conceive.