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Prenatal exposure to tobacco and adverse birth outcomes: effect modification by folate intake during pregnancy



Fetal exposure to tobacco increases the risk for many adverse birth outcomes, but whether diet mitigates these risks has yet to be explored. Here, we examined whether maternal folate intake (from foods and supplements) during pregnancy modified the association between prenatal exposure to tobacco and with preterm delivery, small-for-gestational age (SGA) births, or neonatal adiposity.


Mother–child pairs (n = 701) from Healthy Start were included in this analysis. Urinary cotinine was measured at ~ 27 weeks gestation. Diet was assessed using repeated 24-h dietary recalls. Neonatal adiposity (fat mass percentage) was measured via air displacement plethysmography. Interaction was assessed by including a product term between cotinine (< / ≥ limit of detection [LOD]) and folate (< / ≥ 25th percentile [1077 µg/day]) in separate logistic or linear regression models, adjusting for maternal age, race, ethnicity, education, pre-pregnancy body mass index, and infant sex.


Approximately 26% of women had detectable levels of cotinine. Folate intake was significantly lower among women with cotinine ≥ LOD as compared to those with cotinine < LOD (1293 µg/day vs. 1418 µg/day; p = 0.01). Folate modified the association between fetal exposure to tobacco with neonatal adiposity (p for interaction = 0.07) and SGA (p for interaction = 0.07). Among those with lower folate intake, fetal exposure to tobacco was associated with lower neonatal adiposity (mean difference: -2.09%; 95% CI: -3.44, -0.74) and increased SGA risk (OR: 4.99; 95% CI: 1.55, 16.14). Conversely, among those with higher folate intake, there was no difference in neonatal adiposity (mean difference: -0.17%; 95% CI: -1.13, 0.79) or SGA risk (OR: 1.15; 95% CI: 0.57, 2.31).


Increased folate intake during pregnancy (from foods and/or supplements) may mitigate the risk of fetal growth restriction among those who are unable to quit smoking or cannot avoid secondhand smoke during pregnancy.


Fetal exposure to tobacco (where the mother was an active or secondhand smoker) has been consistently linked to preterm delivery, [1] small-for-gestational age (SGA) at birth, [2, 3] and reduced neonatal adiposity (fat mass percentage), [4] followed by over-compensatory postnatal ‘catch up’ growth and metabolic diseases later in life. [5, 6].

Despite the steady decline in smoking rates in the United States, [7] approximately 17.3% of women of reproductive age (18–49 years) and 6.8% of pregnant women are active smokers. [8] Furthermore, ~ 35% of pregnant women are involuntarily exposed to smoke. [9] Therefore, identifying modifiable factors that may mitigate the impacts of this exposure is an important public health priority.

Of particular interest is dietary folate intake (or its synthetic form often taken as a supplement, folic acid). Beyond the well-established benefit of preventing neural tube defects, [10] evidence has been mounting that folate also may protect against various other adverse birth outcomes. [11] Furthermore, higher overall diet quality during pregnancy may lower the risk for preterm births, [12] SGA births, [13] and lower neonatal adiposity. [14] However, few published studies have examined whether maternal folate intake or overall diet quality during pregnancy may modify the associations between prenatal tobacco exposure and adverse birth outcomes.

To address this gap in knowledge, we leveraged data from Healthy Start, a well-characterized, racially and ethnically-diverse cohort of pregnant women and their children. We hypothesized that the associations between prenatal tobacco exposure and SGA births, preterm births, and neonatal adiposity would be stronger among those with lower folate intake and poorer overall diet quality during pregnancy.


Study design

Data from the Healthy Start cohort were utilized for this secondary data analysis. Briefly, Healthy Start began as a study to better understand fuel-mediated programming of offspring adiposity (NCT02273297)—although in later years expanded to explore an array of environmental and early life exposures associated with a range of infant and childhood outcomes. Study participants were pregnant women (≥ 16 years) who were patients at obstetrics clinics at the University of Colorado Hospital (< 24 weeks gestation). Exclusion criteria included: multiple gestation pregnancies; previous stillbirth or preterm birth at < 25 weeks gestation; preexisting diabetes; asthma; cancer; or psychiatric illness. Women were invited to participate in two in-person research visits during pregnancy (median: 17 and 27 weeks gestation) and one soon after delivery.

Exposure assessment

Urinary cotinine (a metabolite of nicotine and marker of tobacco exposure [15]) was measured in a subsample of study participants at ~ 27 weeks gestation. Cotinine was analyzed in stored urine samples via solid phase competitive ELISA—with a sensitivity of 1 ng/mL (Calbiotech Cotinine ELISA CO096D, Calbiotech, El Cajon, California). Following a previous Healthy Start analysis examining similar exposures, [16] cotinine concentrations were categorized as follows: no exposure (< limit of detection [LOD]); ~ 0.05 ng/mL), maternal exposure to secondhand smoke (cotinine ≥ LOD to 550 ng/mL), and active maternal smoking (≥ 550 ng/mL; an established cut-point for active smoking [17]). Very few women were active smokers (~ 6%). Therefore, cotinine was dichotomized as no exposure (< LOD; 74%) and any exposure to tobacco (≥ LOD; 26%) to maximize power in our interaction analyses.

Birth outcomes

Preterm births were defined as births < 37 weeks completed gestation. SGA status was estimated with sex-, race/ethnic-, and parity-specific growth curves based on the methods by Zhang and Bowes, [18] and Overpeck et al. [19] Fat mass and fat-free mass were measured within 72 h of delivery using the PEA POD (COSMED, Rome, Italy)—an air displacement plethysmography method that uses densitometric techniques to estimate fat mass from the direct measurement of mass and volume. [20] Each infant had two measurements taken with a third measurement taken if the fat mass differed by > 2.0%. The mean of the two closest measurements for each visit was utilized for analysis. Neonatal adiposity (fat mass percentage) was calculated as a proportion of the fat mass divided by total mass. [21].


Maternal age was calculated based on index offspring delivery date and maternal date of birth. Women self-reported maternal education and race/ethnicity via self-report on questionnaires during the 17-week (first research) visit. Maternal pre-pregnancy body mass index (BMI) was assessed as pre-pregnancy weight (kg) divided by height squared (m2) (pre-pregnancy weight obtained from self-report at first research visit (16.2%) or medical records (83.7%) and maternal height measured at first research visit [22]).

The Healthy Eating Index

Maternal diet was assessed using dietary recalls conducted via the Automated Self-Administered 24-Hour Dietary Recall web-based tool during pregnancy, with a range of 1–8 dietary recalls completed by each study participant (median, 2 recalls). Diet data was processed by the Nutrition and Obesity Research Center at University of North Carolina at Chapel Hill. Maternal diet quality was ascertained via the Healthy Eating Index (HEI-2010). [22] Briefly, the HEI-2010 is a diet quality scoring system developed by the US Department of Agriculture, Center for Nutrition Policy and Promotion and the National Cancer Institute (NCI) that was designed to capture adherence of the 2010 Dietary Guidelines for Americans. The tool contains 12 components [1] total vegetables, 2) greens and beans, 3) fruit, 4) whole fruit, 5) whole grains, 6) dairy, 7) total protein foods, 8) seafood and plant proteins, 9) fatty acids, 10) sodium, 11) refined grains, and 12) empty calories) scored per 1000 kcal to give a maximum score of 100 [22] (alcohol intake was not included as all participants had < 13 g per 1000 kcal in each recall (the threshold for alcohol caloric intake inclusion [22])) and has been found to be a valid and reliable measure of diet quality. [23] The HEI-2010 values in our cohort ranged from 33–87. We assessed HEI-2010 values as both a continuous and dichotomous variable (< 61 [the median value]; ≥ 61).

Maternal folate intake

In addition to the dietary recalls, mothers also self-reported supplement use (prenatal, multivitamin or other single nutrient) at each research visit. Folate intake from supplements was calculated by querying brand, type, and dose. [24] Participants described their supplement use within 12 weeks prior to conception (for the first pregnancy visit) or since their last visit (for mid-pregnancy and delivery visits). [25] Total maternal folate/folic acid intake was determined by combining usual daily intake of folate/folic acid from dietary sources and supplements. While the current estimated average total folate requirement for pregnant women (including both dietary and supplemental sources) is ~ 520 µg/day, [26] less than 5% of our population fell below this range. Therefore, we opted to examine folate both continuously and also categorized according to the following selected percentile cut-points (i.e. 50th (< / ≥ 1384 µg/day), 25th (< / ≥ 1077 µg/day), 10th (< / ≥ 872 µg/day), and 5th (< / ≥ 717 µg/day)).

Statistical analysis

A linear regression model was used to examine the main effect association between prenatal tobacco exposure (no exposure, secondhand smoke exposure, and active maternal smoking) and neonatal adiposity (percent fat mass). Logistic regression models estimated the main effect association between prenatal tobacco exposure and categorical outcomes (preterm delivery and SGA births). Interaction was assessed by introducing a product term between the dichotomized cotinine variable (< LOD, ≥ LOD) and continuous or dichotomous diet variables in the separate regression models. Directed acyclic graphs (DAGS) and previous literature findings were used to determine model covariates, which included maternal age, education, race and ethnicity, pre-pregnancy BMI, and infant sex. An alpha level of 0.05 was used to determine statistical significance. As total caloric intake is also associated with each of our outcomes, we also considered maternal average daily caloric intake throughout pregnancy in each of the models as a sensitivity analysis. All statistical analyses were performed using SAS© OnDemand for Academics.


Of the initial cohort of 1410 participants, we excluded 689 participants with missing cotinine data and 20 with missing gestational age measurements. Therefore, 701 mother–child pairs were included in the preterm birth/SGA analysis. Of these, 91 infants were missing PEA POD measurements at birth. Therefore, 630 mother–child pairs were included in the neonatal adiposity analyses. As previously described, [27] no meaningful differences in maternal or child characteristics were detected between the entire cohort and the cotinine subsample of ~ 700 mother–child pairs.

Among both analytic samples, ~ 74% of subjects had little to no cotinine exposure, ~ 20% had cotinine levels equivalent to secondhand smoke exposure, and ~ 6% had cotinine exposure in the active smoking range (Table 1). Both active smokers and those exposed to secondhand smoke tended to be younger, had a lower household income (< $40,000), lower levels of education (≤ a high school education), higher total caloric intake, lower HEI levels, and had lower mean intakes of folate/folic acid (~ 1400 µg/day among non-smokers versus ~ 1300 µg/day among smokers and those exposed to secondhand smoke).

Table 1 Characteristics of mother–child pairs, according to urinary cotinine in pregnancy, healthy start (2010–2014)

Compared to those with high intakes of folate or high diet quality during pregnancy, mothers with lower folate intakes or lower diet quality during pregnancy were younger, had higher BMIs, were less likely to identify a non-Hispanic White, had lower household incomes, and were less educated (Supplemental Table S1). Mothers were higher folate intakes had higher caloric intakes, whereas mothers with higher diet quality during pregnancy had lower caloric intakes.

Compared to offspring with no prenatal tobacco exposure, offspring born to women with cotinine levels indicating active smoking were significantly more likely to be born SGA (aOR: 6.43; 95% CI: 2.89, 14.35) (Table 2). Prenatal tobacco exposure is associated with a slight reduction in neonatal adiposity (adjusted beta for SHS: -0.44; 95% CI: -1.30, 0.41; adjusted beta for active smoking: -0.97; 95% CI: -1.64, -0.30). Prenatal tobacco exposure was not associated with an increased risk for preterm delivery.

Table 2 Adjusted odds ratios and mean/beta coefficients for maternal cotinine categories and selected birth outcomes, Healthy Start (2010–2014)

Our interaction results revealed that maternal folate intake may modify of the association between prenatal tobacco exposure with neonatal adiposity (p for interaction = 0.07) and SGA (p for interaction = 0.07) (Table 3). For instance, among those with lower folate intake (< 25th percentile [< 1077 µg/day]), fetal exposure to tobacco was associated with lower neonatal adiposity (adjusted beta -2.09%; 95% CI: -3.44, -0.74) and increased SGA risk (adjusted odds ratio: 4.99; 95%CI: 1.55, 16.14). Conversely, among those with higher folate intake, there was no difference in neonatal adiposity (adjusted beta -0.17%; 95% CI: -1.13, 0.79) or SGA risk (adjusted odds ratio 1.15; 95%CI: 0.57, 2.31). A similar, albeit non-significant, pattern of interaction between prenatal tobacco exposure and folate on neonatal adiposity was noted across the 10th and 5th percentiles, whereas there was little evidence for interaction across the other folate cut-points (Supplemental Table S2). We found no evidence of effect modification by HEI or folate on the associations between prenatal tobacco exposure and preterm births (Table 3). Our results were similar following adjustment for prenatal daily total caloric intake (data not shown).

Table 3 Adjusted odds ratios and mean/beta coefficients for maternal cotinine categories and selected birth outcomes by maternal dietary factors, Healthy Start (2010–2014)


Our findings suggest that dietary folate minimizes the risk of tobacco-induced fetal growth restriction. By contrast, overall diet quality during pregnancy did not modify the risk for adverse birth outcomes. Given that many pregnant women are unable to successfully quit smoking [28] or are involuntarily exposed to SHS [29], our findings may have important public health implications for mitigating risks associated with this exposure.

Our interaction findings may provide insights about the mechanisms underlying the associations between prenatal tobacco exposure and systematic growth restriction. One key pathway may involve maternal and fetal oxidative stress. Tobacco is known to increase markers of oxidative stress in the placenta via specific epigenomic modulations in key metabolic pathways. [30] Conversely, folate exhibits antioxidant [31] and anti-inflammatory properties [32]which may independently improve fetal growth [31].

A more novel mechanistic pathway may involve tobacco-induced disruption of the homocysteine-methionine cycle of the fetus, [33] which is associated with deficiencies in circulating folate. Tobacco use during pregnancy is known to increase maternal homocysteine [34], which is associated with impaired uteroplacental blood flow and fetal growth restriction. [35] These effects may be offset by maintaining adequate dietary folate intake. [36] This hypothesis is supported by the work of Bakker and colleagues, [37] who reported that the combination of prenatal tobacco exposure and higher maternal homocysteine concentrations is associated with lower birth weight, but not preterm delivery.

Our interaction findings may have the potential for a large and immediate public health impact. Pregnant women have a heightened interest in dietary information [38] and are particularly receptive to dietary counseling during prenatal care. [39] Pregnant women are already encouraged to consume adequate folate to reduce the risk for neural tube defects, [10] and most do. [24] Overall, our findings support the positive impacts of maternal folate intakes during pregnancy on improving fetal growth.

Contrary to previous studies [40, 41], we found no evidence that overall diet quality mitigated the risk of prenatal tobacco exposure on the adverse birth outcomes. [40, 41]There are several factors that could explain this discrepancy. First, diet quality was captured via a Mediterranean diet score in previous studies [40, 41], whereas we utilized the Healthy Eating Index. Second, our study population had a relatively high diet quality as compared to the national population (median HEI in our study population was 61, whereas data from the National Health and Nutrition Examination Survey reports a median HEI of 52 [42]. Finally, our interaction findings with folate intake provides points to specific mechanisms (e.g. homocysteine pathways) that may not be reflected in measures of overall diet quality.

One limitation of our approach is the one-time measurement of cotinine. This prohibited our ability to examine trimester-specific effects, which have been noted in previous studies. [43] Additionally, since cotinine has a relatively short half-life [44], our one-time assessment may not be an accurate representation of tobacco exposure throughout pregnancy. [44] Our categorization of cotinine (< / > 550 mg/mL) is a highly sensitive but less specific cut-point for distinguishing active smokers from passive smokers. This may have resulted in some exposure misclassification. We speculate that the exposure misclassification would nondifferential with respect to the outcome, thus our effect estimates would be biased towards the null.

While many maternal-infant factors were controlled for in our analyses, residual confounding cannot be ruled out. Additionally, the small number of offspring born preterm or SGA births may have hindered our ability to detect an interaction between tobacco and diet. Lastly, our ability to generalize findings to other populations is limited, as mothers in our cohort may have had higher education levels, higher diet quality during pregnancy, and lower BMI levels than the general population.

Some of the novel aspects of the study include our ability to limit information bias. First, we utilized air displacement plethysmography, which has been shown to be a convenient, reliable, and valid method for measuring neonatal body composition. [20] With respect to nutrition, maternal folate intake was determined by both dietary recalls and self-reported supplement use, which provides a more complete picture of folate consumed during pregnancy than relying on dietary recall alone. Additionally, our use of repeated dietary recalls may have minimized recall bias [25] by giving participants more than one opportunity to report previously forgotten food items and estimate portion sizes. [45] Yet, there is still some potential for measurement error, since most of the women in our study completed only two dietary recalls, and may have misrepresented or completely omitted the amounts of certain foods/beverages consumed. [46, 25, 22, 47].


Despite the widely communicated risks of smoking during pregnancy, many pregnant women smoke or are involuntarily exposed to SHS. [48] This is concerning, given the well-documented associations between prenatal tobacco exposure on systematic growth restriction of the fetus. There is a need to identify modifiable factors, such as folate intake during pregnancy (increased via diet or folic acid supplementation), that may protect the fetus against these environmental insults. Our results suggest that higher levels of folate intake during pregnancy (≥ 1077 µg/day) may limit the effects of prenatal tobacco exposure on systematic growth restriction. Our findings point to increasing overall folate intake as a potential mitigation strategy among pregnant women who are unable to avoid SHS or quit smoking during pregnancy.

Availability of data and material

The dataset analyzed in this study is protected under an institution review board protocol and is not available for distribution.



Adverse birth outcome


One-way analysis by variance


Body Mass Index


Directed acyclic graphs


Fat-free mass


Fat mass


Healthy Eating Index


Limit of detection


National Cancer Institute


Small-for-gestational age


Secondhand smoke


  1. Liu B, Xu G, Sun Y, Qiu X, Ryckman KK, Yu Y, et al. Maternal cigarette smoking before and during pregnancy and the risk of preterm birth: A dose–response analysis of 25 million mother–infant pairs. PLOS Medicine. 2020;17(8):e1003158.

    Article  CAS  Google Scholar 

  2. Kobayashi S, Sata F, Hanaoka T, Braimoh TS, Ito K, Tamura N, et al. Association between maternal passive smoking and increased risk of delivering small-for-gestational-age infants at full-term using plasma cotinine levels from The Hokkaido Study: a prospective birth cohort. BMJ Open. 2019;9(2): e023200.

    Article  Google Scholar 

  3. Sabra S, Gratacós E, Gómez Roig MD. Smoking-Induced Changes in the Maternal Immune, Endocrine, and Metabolic Pathways and Their Impact on Fetal Growth: A Topical Review. Fetal Diagn Ther. 2017;41(4):241–50.

    Article  Google Scholar 

  4. Harrod CS, Fingerlin TE, Chasan-Taber L, Reynolds RM, Glueck DH, Dabelea D. Exposure to prenatal smoking and early-life body composition: the healthy start study. Obesity (Silver Spring). 2015;23(1):234–41.

    Article  Google Scholar 

  5. Harrod CS, Fingerlin TE, Chasan-Taber L, Reynolds RM, Glueck DH, Dabelea D. Exposure to prenatal smoking and early-life body composition: the healthy start study. Obesity (Silver Spring). 2015;23(1):234–41.

    Article  Google Scholar 

  6. Adair LS. Size at birth and growth trajectories to young adulthood. Am J Hum Biol. 2007;19(3):327–37.

    Article  Google Scholar 

  7. Warren GW, Alberg AJ, Kraft AS, Cummings KM. The 2014 Surgeon General’s report: “The Health Consequences of Smoking–50 Years of Progress”: A paradigm shift in cancer care. Cancer. 2014;120(13):1914–6.

    Article  Google Scholar 

  8. Mazurek JM, England LJ. Cigarette Smoking Among Working Women of Reproductive Age-United States, 2009–2013. Nicotine Tob Res. 2016;18(5):894–9.

    Article  Google Scholar 

  9. WHO. World Health Organization report on the global tobacco epidemic, 2009: implementing smoke-free environments. Geneva (CH). 2009.

  10. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009 -05–05;150(9):626–631.

  11. Deshmukh U, Katre P, Yajnik CS. Influence of maternal vitamin B12 and folate on growth and insulin resistance in the offspring. Nestle Nutr Inst Workshop Ser. 2013;74:145–56.

    Article  Google Scholar 

  12. Mantovani E, Filippini F, Bortolus R, Franchi M. Folic Acid Supplementation and Preterm Birth: Results from Observational Studies. Biomed Res Int 2014;2014.

  13. Okubo H, Miyake Y, Sasaki S, Tanaka K, Murakami K, Hirota Y, et al. Maternal dietary patterns in pregnancy and fetal growth in Japan: the Osaka Maternal and Child Health Study. Br J Nutr. 2012;107(10):1526–33.

    Article  CAS  Google Scholar 

  14. Leary SD, Smith GD, Rogers IS, Reilly JJ, Wells JC, Ness AR. Smoking during pregnancy and offspring fat and lean mass in childhood. Obesity (Silver Spring). 2006;14(12):2284–93.

    Article  Google Scholar 

  15. Zenzes MT, Reed TE, Wang P, Klein J. Cotinine, a major metabolite of nicotine, is detectable in follicular fluids of passive smokers in in vitro fertilization therapy. Fertil Steril. 1996;66(4):614–9.

    Article  CAS  Google Scholar 

  16. Moore BF, Starling AP, Magzamen S, Harrod CS, Allshouse WB, Adgate JL, et al. Fetal exposure to maternal active and secondhand smoking with offspring early-life growth in the Healthy Start study. Int J Obes (Lond). 2019;43(4):652–62.

    Article  CAS  Google Scholar 

  17. Zielińska-Danch W, Wardas W, Sobczak A, Szołtysek-Bołdys I. Estimation of urinary cotinine cut-off points distinguishing non-smokers, passive and active smokers. Biomarkers. 2007;12(5):484–96.

    Article  Google Scholar 

  18. Zhang J, Bowes WA. Birth-weight-for-gestational-age patterns by race, sex, and parity in the United States population. Obstet Gynecol. 1995;86(2):200–8.

    Article  CAS  Google Scholar 

  19. Overpeck MD, Hediger ML, Zhang J, Trumble AC, Klebanoff MA. Birth weight for gestational age of Mexican American infants born in the United States. Obstet Gynecol. 1999;93(6):943–7.

    CAS  PubMed  Google Scholar 

  20. Mazahery H, von Hurst PR, McKinlay CJD, Cormack BE, Conlon CA. Air displacement plethysmography (pea pod) in full-term and pre-term infants: a comprehensive review of accuracy, reproducibility, and practical challenges. Matern Health Neonatol Perinatol. 2018;4:12.

    Article  Google Scholar 

  21. Moore BF, Harrall KK, Sauder KA, Glueck DH, Dabelea D. Neonatal Adiposity and Childhood Obesity. Pediatrics. 2020;146(3):e20200737.

    Article  Google Scholar 

  22. Shapiro ALB, Kaar JL, Crume TL, Starling AP, Siega-Riz AM, Ringham BM, et al. Maternal diet quality in pregnancy and neonatal adiposity: the Healthy Start Study. Int J Obes (Lond). 2016;40(7):1056–62.

    Article  CAS  Google Scholar 

  23. Guenther PM, Kirkpatrick SI, Reedy J, Krebs-Smith SM, Buckman DW, Dodd KW, et al. The Healthy Eating Index-2010 is a valid and reliable measure of diet quality according to the 2010 Dietary Guidelines for Americans. J Nutr. 2014;144(3):399–407.

    Article  CAS  Google Scholar 

  24. Sauder KA, Harte RN, Ringham BM, Guenther PM, Bailey RL, Alshawabkeh A, et al. Disparities in Risks of Inadequate and Excessive Intake of Micronutrients during Pregnancy. J Nutr. 2021;151(11):3555–69.

    Article  Google Scholar 

  25. Sauder KA, Starling AP, Shapiro AL, Kaar JL, Ringham BM, Glueck DH, et al. Exploring the association between maternal prenatal multivitamin use and early infant growth: The Healthy Start Study. Pediatr Obes. 2016;11(5):434–41.

    Article  CAS  Google Scholar 

  26. Folate, Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on, Vitamins OB, Choline A. Folate. : National Academies Press (US); 1998.

  27. Moore BF, Starling AP, Magzamen S, Harrod CS, Allshouse WB, Adgate JL, et al. Fetal exposure to maternal active and secondhand smoking with offspring early-life growth in the Healthy Start study. Int J Obes (Lond). 2019;43(4):652–62.

    Article  CAS  Google Scholar 

  28. Soneji S, Beltrán-Sánchez H. Association of Maternal Cigarette Smoking and Smoking Cessation With Preterm Birth. JAMA Netw Open. 2019;2(4):e192514.

    Article  Google Scholar 

  29. Tsai J. Exposure to Secondhand Smoke Among Nonsmokers — United States, 1988–2014. MMWR Morb Mortal Wkly Rep 2018;67.

  30. Sbrana E, Suter MA, Abramovici AR, Hawkins HK, Moss JE, Patterson L, et al. Maternal tobacco use is associated with increased markers of oxidative stress in the placenta. Am J Obstet Gynecol. 2011;205(3):246.e1-7.

    Article  Google Scholar 

  31. Ebisch IMW, Thomas CMG, Peters WHM, Braat DDM, Steegers-Theunissen RPM. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Update. 2007;13(2):163–74.

    Article  CAS  Google Scholar 

  32. Jones P, Lucock M, Scarlett CJ, Veysey M, Beckett EL. Folate and Inflammation – links between folate and features of inflammatory conditions. J Nutr Intermed Metab. 2019;18:100104.

    Article  Google Scholar 

  33. Wersch JW, Janssens Y, Zandvoort JA. Folic acid, Vitamin B(12), and homocysteine in smoking and non-smoking pregnant women. Eur J Obstet Gynecol Reprod Biol. 2002;103(1):18–21.

    Article  Google Scholar 

  34. Tuenter A, Bautista Nino PK, Vitezova A, Pantavos A, Bramer WM, Franco OH, et al. Folate, vitamin B12, and homocysteine in smoking-exposed pregnant women: A systematic review. Matern Child Nutr. 2019;15(1):e12675.

    Article  Google Scholar 

  35. Brauer PR, Tierney BJ. Consequences of elevated homocysteine during embryonic development and possible modes of action. Curr Pharm Des. 2004;10(22):2719–32.

    Article  CAS  Google Scholar 

  36. Riddell LJ, Chisholm A, Williams S, Mann JI. Dietary strategies for lowering homocysteine concentrations. Am J Clin Nutr. 2000;71(6):1448–54.

    Article  CAS  Google Scholar 

  37. Bakker R, Timmermans S, Steegers EAP, Hofman A, Jaddoe VWV. Folic Acid Supplements Modify the Adverse Effects of Maternal Smoking on Fetal Growth and Neonatal Complications. J Nutr. 2011;141(12):2172–9.

    Article  CAS  Google Scholar 

  38. Szwajcer EM, Hiddink GJ, Maas L, Koelen MA, van Woerkum, Cees M. J. Nutrition-related information-seeking behaviours of women trying to conceive and pregnant women: evidence for the life course perspective. Fam Pract 2008 -12;25 Suppl 1:99.

  39. May L, Suminski R, Berry A, Linklater E, Jahnke S. Diet and Pregnancy: Health-Care Providers and Patient Behaviors. J Perinat Educ. 2014;23(1):50–6.

    Article  Google Scholar 

  40. Smith LK, Draper ES, Evans TA, Field DJ, Johnson SJ, Manktelow BN, et al. Associations between late and moderately preterm birth and smoking, alcohol, drug use and diet: a population-based case–cohort study. Arch Dis Child Fetal Neonatal Ed. 2015;100(6):F486–91.

    Article  Google Scholar 

  41. Martínez-Galiano JM, Amezcua-Prieto C, Cano-Ibañez N, Olmedo-Requena R, Jiménez-Moleón JJ, Bueno-Cavanillas A, et al. Diet as a counteracting agent of the effect of some well-known risk factors for small for gestational age. Nutrition. 2020;72.

    Article  Google Scholar 

  42. Davis BJK, Bi X, Higgins KA, Scrafford CG. Gestational Health Outcomes Among Pregnant Women in the United States by Level of Dairy Consumption and Quality of Diet, NHANES 2003–2016. Matern Child Health J 2022 -08–08.

  43. Miyake Y, Tanaka K, Arakawa M. Active and passive maternal smoking during pregnancy and birth outcomes: the Kyushu Okinawa Maternal and Child Health Study. BMC Pregnancy and Childbirth volume 2013;13(157).

  44. Benowitz NL. Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev. 1996;18(2):188–204.

    Article  CAS  Google Scholar 

  45. Gibson RS, Charrondiere UR, Bell W. Measurement Errors in Dietary Assessment Using Self-Reported 24-Hour Recalls in Low-Income Countries and Strategies for Their Prevention. Advances in Nutrition. 2017;8(6):980–91.

    Article  Google Scholar 

  46. Shim J, Oh K, Kim HC. Dietary assessment methods in epidemiologic studies. Epidemiol Health. 2014;36:e2014009.

    Article  Google Scholar 

  47. Bailey RL, Fulgoni VL, Taylor CL, Pfeiffer CM, Thuppal SV, McCabe GP, et al. Correspondence of folate dietary intake and biomarker data123. Am J Clin Nutr. 2017;105(6):1336–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Reese S, Morgan C, Parascandola M, et al. Secondhand smoke exposure during pregnancy: a cross-sectional analysis of data from Demographic and Health Survey from 30 low-income and middle-income countries. Tob Control. 2019;28:420–6.

    Article  Google Scholar 

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We would like to thank the researchers at CU School of Public Health for providing access and transfer of the dataset and biospecimen results used for this research. Additionally, we are thankful to the mothers and children of Healthy Start for participating in this study. This work was supported by the National Institutes of Health (R01DK076648, UH3OD023248, R01ES022934, R01GM121081, R00ES028711).

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This work was supported by the National Institutes of Health (R01DK076648, UH3OD023248, R01ES022934, R00ES028711, UL1TR003167).

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Authors and Affiliations



ATH designed the project, conducted the analysis, interpreted the data, wrote the manuscript write-up, and finalized the manuscript for journal submission. AVW, PHL, CAG, and NR assisted with project planning, interpretation of the data, and provided feedback on the manuscript. DD designed the Healthy Start study and provided feedback on the interpretation of the study findings. BFM oversaw the design, analysis, and interpretation, and provided feedback on each draft of the manuscript. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Brianna F. Moore.

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Not applicable. Protocols for enrollment and biospecimen collection were approved by the Colorado Multiple Institutional Review Board (#09–0563). The present study has been approved by the University of Texas Health Science Center Committee for the Protection of Human Subjects (HSC-SPH-20–0080, Principal Investigator: Dr. Brianna Moore).

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Supplemental Table S1. Maternal characteristics, according to supplementation intake and dietary factors, Healthy Start (2010-2014). Supplemental Table S2. Adjusted odds ratios and mean/beta coefficients for maternal cotinine categories and selected birth outcomes by maternal total dietary folate intake, Healthy Start (2010-2014).

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Hoyt, A.T., Wilkinson, A.V., Langlois, P.H. et al. Prenatal exposure to tobacco and adverse birth outcomes: effect modification by folate intake during pregnancy. matern health, neonatol and perinatol 8, 6 (2022).

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