Association Between Maternal Caffeine Consumption and Metabolism and Neonatal Anthropometry: A Secondary Analysis of the NICHD Fetal Growth Studies–Singletons | Neonatology | JAMA Network Open | JAMA Network
[Skip to Navigation]
Table 1.  Sample Characteristics by Plasma Caffeine Quartiles, Fetal Growth Study–Singletons (N = 2055)
Sample Characteristics by Plasma Caffeine Quartiles, Fetal Growth Study–Singletons (N = 2055)
Table 2.  Associations Between Caffeine and Paraxanthine Quartiles and Neonatal Anthropometric Measures, NICHD Fetal Growth Studies–Singletons (N = 2055)a
Associations Between Caffeine and Paraxanthine Quartiles and Neonatal Anthropometric Measures, NICHD Fetal Growth Studies–Singletons (N = 2055)a
Table 3.  Associations Between Continuous Caffeine and Paraxanthine Plasma Concentrations and Neonatal Anthropometric Measures, NICHD Fetal Growth Studies–Singletons (N = 2055)a
Associations Between Continuous Caffeine and Paraxanthine Plasma Concentrations and Neonatal Anthropometric Measures, NICHD Fetal Growth Studies–Singletons (N = 2055)a
Table 4.  The aRR of Small for Gestational Age for Plasma Caffeine and Paraxanthine Quartiles, NICHD Fetal Growth Studies–Singletons (N = 2055)a
The aRR of Small for Gestational Age for Plasma Caffeine and Paraxanthine Quartiles, NICHD Fetal Growth Studies–Singletons (N = 2055)a
Table 5.  Associations Between Self-reported Caffeine Consumption and Various Neonatal Outcomes (N = 2101)a,b
Associations Between Self-reported Caffeine Consumption and Various Neonatal Outcomes (N = 2101)a,b
1.
ACOG Committee.  ACOG Committee Opinion No. 462: moderate caffeine consumption during pregnancy.   Obstet Gynecol. 2010;116(2 Pt 1):467-468.PubMedGoogle Scholar
2.
Rhee  J, Kim  R, Kim  Y,  et al.  Maternal caffeine consumption during pregnancy and risk of low birth weight: a dose-response meta-analysis of observational studies.   PLoS One. 2015;10(7):e0132334. doi:10.1371/journal.pone.0132334 PubMedGoogle Scholar
3.
Chen  L-W, Wu  Y, Neelakantan  N, Chong  MF-F, Pan  A, van Dam  RM.  Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose-response meta-analysis.   BMC Med. 2014;12(1):174. doi:10.1186/s12916-014-0174-6 PubMedGoogle ScholarCrossref
4.
Group  C; CARE Study Group.  Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study.   BMJ. 2008;337:a2332. doi:10.1136/bmj.a2332 PubMedGoogle ScholarCrossref
5.
Bakker  R, Steegers  EA, Obradov  A, Raat  H, Hofman  A, Jaddoe  VW.  Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: the Generation R Study.   Am J Clin Nutr. 2010;91(6):1691-1698. doi:10.3945/ajcn.2009.28792 PubMedGoogle ScholarCrossref
6.
Grosso  LM, Rosenberg  KD, Belanger  K, Saftlas  AF, Leaderer  B, Bracken  MB.  Maternal caffeine intake and intrauterine growth retardation.   Epidemiology. 2001;12(4):447-455. doi:10.1097/00001648-200107000-00015 PubMedGoogle ScholarCrossref
7.
Bracken  MB, Triche  EW, Belanger  K, Hellenbrand  K, Leaderer  BP.  Association of maternal caffeine consumption with decrements in fetal growth.   Am J Epidemiol. 2003;157(5):456-466. doi:10.1093/aje/kwf220 PubMedGoogle ScholarCrossref
8.
Poole  R, Ewings  S, Parkes  J, Fallowfield  JA, Roderick  P.  Misclassification of coffee consumption data and the development of a standardised coffee unit measure.   BMJ Nutr Prev Health. 2019;2(1):11-19. doi:10.1136/bmjnph-2018-000013 PubMedGoogle ScholarCrossref
9.
de Medeiros  TS  Jr, Bernardi  JR, de Brito  ML, Bosa  VL, Goldani  MZ, da Silva  CH.  Caffeine intake during pregnancy in different intrauterine environments and its association with infant anthropometric measurements at 3 and 6 months of age.   Matern Child Health J. 2017;21(6):1297-1307. doi:10.1007/s10995-016-2230-7 PubMedGoogle ScholarCrossref
10.
Sasaki  S, Limpar  M, Sata  F, Kobayashi  S, Kishi  R.  Interaction between maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido study.   Pediatr Res. 2017;82(1):19-28. doi:10.1038/pr.2017.70 PubMedGoogle ScholarCrossref
11.
Grosso  LM, Triche  EW, Belanger  K, Benowitz  NL, Holford  TR, Bracken  MB.  Caffeine metabolites in umbilical cord blood, cytochrome P-450 1A2 activity, and intrauterine growth restriction.   Am J Epidemiol. 2006;163(11):1035-1041. doi:10.1093/aje/kwj125 PubMedGoogle ScholarCrossref
12.
Grewal  J, Grantz  KL, Zhang  C,  et al.  Cohort profile: NICHD Fetal Growth Studies-Singletons and Twins.   Int J Epidemiol. 2018;47(1):25-25l. doi:10.1093/ije/dyx161 PubMedGoogle ScholarCrossref
13.
Buck Louis  GM, Grewal  J, Albert  PS,  et al.  Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies.   Am J Obstet Gynecol. 2015;213(4):449.e1-449.e41. doi:10.1016/j.ajog.2015.08.032 PubMedGoogle ScholarCrossref
14.
Doull  IJ, McCaughey  ES, Bailey  BJ, Betts  PR.  Reliability of infant length measurement.   Arch Dis Child. 1995;72(6):520-521. doi:10.1136/adc.72.6.520 PubMedGoogle ScholarCrossref
15.
Shinwell  ES, Shlomo  M.  Measured length of normal term infants changes over the first two days of life.   J Pediatr Endocrinol Metab. 2003;16(4):537-540. doi:10.1515/JPEM.2003.16.4.537 PubMedGoogle ScholarCrossref
16.
Pereira-Da-Silva  L, Bergmans  KI, van Kerkhoven  LA, Leal  F, Virella  D, Videira-Amaral  JM.  Reducing discomfort while measuring crown-heel length in neonates.   Acta Paediatr. 2006;95(6):742-746. doi:10.1080/08035250500516623 PubMedGoogle ScholarCrossref
17.
Catalano  PM, Thomas  AJ, Avallone  DA, Amini  SB.  Anthropometric estimation of neonatal body composition.   Am J Obstet Gynecol. 1995;173(4):1176-1181. doi:10.1016/0002-9378(95)91348-3 PubMedGoogle ScholarCrossref
18.
National Health and Nutrition Examination Survey. Anthropometry Procedures Manual. Published January 2007. Accessed February 23, 2021. https://www.cdc.gov/nchs/data/nhanes/nhanes_07_08/manual_an.pdf
19.
Williams  AM, Brain  JL.  The normal position of the umbilicus in the newborn: an aid to improving the cosmetic result in exomphalos major.   J Pediatr Surg. 2001;36(7):1045-1046. doi:10.1053/jpsu.2001.24737 PubMedGoogle ScholarCrossref
20.
Stetzer  BP, Thomas  A, Amini  SB, Catalano  PM.  Neonatal anthropometric measurements to predict birth weight by ultrasound.   J Perinatol. 2002;22(5):397-402. doi:10.1038/sj.jp.7210754 PubMedGoogle ScholarCrossref
21.
Fok  TF, Hon  KL, Wong  E,  et al; Hong Kong Neonatal Measurements Working Group.  Trunk anthropometry of Hong Kong Chinese infants.   Early Hum Dev. 2005;81(9):781-790. doi:10.1016/j.earlhumdev.2005.06.002 PubMedGoogle ScholarCrossref
22.
Rodríguez  G, Samper  MP, Ventura  P, Pérez-González  JM.  Sex-specific charts for abdominal circumference in term and near-term Caucasian newborns.   J Perinat Med. 2008;36(6):527-530. doi:10.1515/JPM.2008.077 PubMedGoogle ScholarCrossref
23.
de Onis  M, Onyango  AW, Van den Broeck  J, Chumlea  WC, Martorell  R.  Measurement and standardization protocols for anthropometry used in the construction of a new international growth reference.   Food Nutr Bull. 2004;25(1)(suppl):S27-S36. doi:10.1177/15648265040251S105 PubMedGoogle ScholarCrossref
24.
Johnson  TS, Engstrom  JL, Gelhar  DK.  Intra- and interexaminer reliability of anthropometric measurements of term infants.   J Pediatr Gastroenterol Nutr. 1997;24(5):497-505. doi:10.1097/00005176-199705000-00001 PubMedGoogle ScholarCrossref
25.
Ulijaszek  SJ, Kerr  DA.  Anthropometric measurement error and the assessment of nutritional status.   Br J Nutr. 1999;82(3):165-177. doi:10.1017/S0007114599001348 PubMedGoogle ScholarCrossref
26.
Catalano  PM, Mele  L, Landon  MB,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.  Inadequate weight gain in overweight and obese pregnant women: what is the effect on fetal growth?   Am J Obstet Gynecol. 2014;211(2):137.e1-137.e7. doi:10.1016/j.ajog.2014.02.004 PubMedGoogle ScholarCrossref
27.
Duryea  EL, Hawkins  JS, McIntire  DD, Casey  BM, Leveno  KJ.  A revised birth weight reference for the United States.   Obstet Gynecol. 2014;124(1):16-22. doi:10.1097/AOG.0000000000000345 PubMedGoogle ScholarCrossref
28.
US Department of Agriculture ARS. FoodData Central. Published 2019. Accessed February 29, 2020. https://fdc.nal.usda.gov/
29.
Ghotbi  R, Christensen  M, Roh  HK, Ingelman-Sundberg  M, Aklillu  E, Bertilsson  L.  Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans.   Eur J Clin Pharmacol. 2007;63(6):537-546. doi:10.1007/s00228-007-0288-2 PubMedGoogle ScholarCrossref
30.
Han  XM, Ouyang  DS, Chen  XP,  et al.  Inducibility of CYP1A2 by omeprazole in vivo related to the genetic polymorphism of CYP1A2.   Br J Clin Pharmacol. 2002;54(5):540-543. doi:10.1046/j.1365-2125.2002.01686.x PubMedGoogle ScholarCrossref
31.
Sachse  C, Brockmöller  J, Bauer  S, Roots  I.  Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine.   Br J Clin Pharmacol. 1999;47(4):445-449. doi:10.1046/j.1365-2125.1999.00898.x PubMedGoogle ScholarCrossref
32.
Richardson  DB, Ciampi  A.  Effects of exposure measurement error when an exposure variable is constrained by a lower limit.   Am J Epidemiol. 2003;157(4):355-363. doi:10.1093/aje/kwf217 PubMedGoogle ScholarCrossref
33.
Schisterman  EF, Vexler  A, Whitcomb  BW, Liu  A.  The limitations due to exposure detection limits for regression models.   Am J Epidemiol. 2006;163(4):374-383. doi:10.1093/aje/kwj039 PubMedGoogle ScholarCrossref
34.
Jin  F, Qiao  C.  Association of maternal caffeine intake during pregnancy with low birth weight, childhood overweight, and obesity: a meta-analysis of cohort studies.   Int J Obes (Lond). 2021;45(2):279-287. doi:10.1038/s41366-020-0617-4PubMedGoogle ScholarCrossref
35.
Brown  LD.  Endocrine regulation of fetal skeletal muscle growth: impact on future metabolic health.   J Endocrinol. 2014;221(2):R13-R29. doi:10.1530/JOE-13-0567 PubMedGoogle ScholarCrossref
36.
Chen  LW, Fitzgerald  R, Murrin  CM, Mehegan  J, Kelleher  CC, Phillips  CM; Lifeways Cross Generation Cohort Study.  Associations of maternal caffeine intake with birth outcomes: results from the Lifeways Cross Generation Cohort Study.   Am J Clin Nutr. 2018;108(6):1301-1308. doi:10.1093/ajcn/nqy219 PubMedGoogle ScholarCrossref
37.
Wierzejska  R, Jarosz  M, Wojda  B.  Caffeine intake during pregnancy and neonatal anthropometric parameters.   Nutrients. 2019;11(4):E806. doi:10.3390/nu11040806 PubMedGoogle Scholar
38.
Hoyt  AT, Browne  M, Richardson  S, Romitti  P, Druschel  C; National Birth Defects Prevention Study.  Maternal caffeine consumption and small for gestational age births: results from a population-based case-control study.   Matern Child Health J. 2014;18(6):1540-1551. doi:10.1007/s10995-013-1397-4 PubMedGoogle ScholarCrossref
39.
Yu  T, Campbell  SC, Stockmann  C,  et al.  Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites.   J Clin Pharmacol. 2016;56(5):590-596. doi:10.1002/jcph.632 PubMedGoogle ScholarCrossref
40.
Zhang  C, Xu  D, Luo  H,  et al.  Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration.   Toxicology. 2014;325:74-84. doi:10.1016/j.tox.2014.08.015 PubMedGoogle ScholarCrossref
41.
Papadopoulou  E, Botton  J, Brantsæter  A-L,  et al.  Maternal caffeine intake during pregnancy and childhood growth and overweight: results from a large Norwegian prospective observational cohort study.   BMJ Open. 2018;8(3):e018895. doi:10.1136/bmjopen-2017-018895 PubMedGoogle Scholar
42.
Reynolds  RM.  Corticosteroid-mediated programming and the pathogenesis of obesity and diabetes.   J Steroid Biochem Mol Biol. 2010;122(1-3):3-9. doi:10.1016/j.jsbmb.2010.01.009 PubMedGoogle ScholarCrossref
43.
Voerman  E, Jaddoe  VW, Hulst  ME, Oei  EH, Gaillard  R.  Associations of maternal caffeine intake during pregnancy with abdominal and liver fat deposition in childhood.   Pediatr Obes. 2020;15(5):e12607. doi:10.1111/ijpo.12607 PubMedGoogle Scholar
44.
Nehlig  A.  Interindividual differences in caffeine metabolism and factors driving consumption.   Pharmacol Rev. 2018;70(2):384-411. doi:10.1124/pr.117.014407 PubMedGoogle ScholarCrossref
45.
Grosso  LM, Triche  E, Benowitz  NL, Bracken  MB.  Prenatal caffeine assessment: fetal and maternal biomarkers or self-reported intake?   Ann Epidemiol. 2008;18(3):172-178. doi:10.1016/j.annepidem.2007.11.005 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    Obstetrics and Gynecology
    March 25, 2021

    Association Between Maternal Caffeine Consumption and Metabolism and Neonatal Anthropometry: A Secondary Analysis of the NICHD Fetal Growth Studies–Singletons

    Author Affiliations
    • 1Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
    • 2Biostatistics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
    • 3Office of the Dean, College of Health and Human Services, George Mason University, Fairfax, Virginia
    • 4The Prospective Group Inc, Fairfax, Virginia
    • 5Department of Pediatrics, New York University School of Medicine, New York
    • 6Department of Environmental Medicine, New York University School of Medicine, New York
    JAMA Netw Open. 2021;4(3):e213238. doi:10.1001/jamanetworkopen.2021.3238
    Key Points

    Question  Is maternal caffeine intake associated with neonatal anthropometry?

    Findings  In this cohort study of 2055 women from 12 clinical sites, measures of caffeine consumption (plasma caffeine and paraxanthine and self-reported consumption) were associated with neonatal size at birth. Increasing caffeine measures were significantly associated with lower birth weight, shorter length, and smaller head, arm, and thigh circumference.

    Meaning  In this study, caffeine consumption during pregnancy, even in amounts less than the recommended 200 mg per day, was associated with smaller neonatal anthropometric measurements.

    Abstract

    Importance  Higher caffeine consumption during pregnancy has been associated with lower birth weight. However, associations of caffeine consumption, based on both plasma concentrations of caffeine and its metabolites, and self-reported caffeinated beverage intake, with multiple measures of neonatal anthropometry, have yet to be examined.

    Objective  To evaluate the association between maternal caffeine intake and neonatal anthropometry, testing effect modification by fast or slow caffeine metabolism genotype.

    Design, Setting, and Participants  A longitudinal cohort study, the National Institute of Child Health and Human Development Fetal Growth Studies–Singletons, enrolled 2055 nonsmoking women at low risk for fetal growth abnormalities with complete information on caffeine consumption from 12 US clinical sites between 2009 and 2013. Secondary analysis was completed in 2020.

    Exposures  Caffeine was evaluated by both plasma concentrations of caffeine and paraxanthine and self-reported caffeinated beverage consumption measured/reported at 10-13 weeks gestation. Caffeine metabolism defined as fast or slow using genotype information from the single nucleotide variant rs762551 (CYP1A2*1F).

    Main Outcomes and Measures  Neonatal anthropometric measures, including birth weight, length, and head, abdominal, arm, and thigh circumferences, skin fold and fat mass measures. The β coefficients represent the change in neonatal anthropometric measure per SD change in exposure.

    Results  A total of 2055 participants had a mean (SD) age of 28.3 (5.5) years, mean (SD) body mass index of 23.6 (3.0), and 580 (28.2%) were Hispanic, 562 (27.4%) were White, 518 (25.2%) were Black, and 395 (19.2%) were Asian/Pacific Islander. Delivery occurred at a mean (SD) of 39.2 (1.7) gestational weeks. Compared with the first quartile of plasma caffeine level (≤28 ng/mL), neonates of women in the fourth quartile (>659 ng/mL) had lower birth weight (β = −84.3 g; 95% CI, −145.9 to −22.6 g; P = .04 for trend), length (β = −0.44 cm; 95% CI, −0.78 to −0.12 cm; P = .04 for trend), and head (β = −0.28 cm; 95% CI, −0.47 to −0.09 cm; P < .001 for trend), arm (β = −0.25 cm; 95% CI, −0.41 to −0.09 cm: P = .02 for trend), and thigh (β = −0.29 cm; 95% CI, −0.58 to −0.04 cm; P = .07 for trend) circumference. Similar reductions were observed for paraxanthine quartiles, and for continuous measures of caffeine and paraxanthine concentrations. Compared with women who reported drinking no caffeinated beverages, women who consumed approximately 50 mg per day (~ 1/2 cup of coffee) had neonates with lower birth weight (β = −66 g; 95% CI, −121 to −10 g), smaller arm (β = −0.17 cm; 95% CI, −0.31 to −0.02 cm) and thigh (β = −0.32 cm; 95% CI, −0.55 to −0.09 cm) circumference, and smaller anterior flank skin fold (β = −0.24 mm; 95% CI, −0.47 to −0.01 mm). Results did not differ by fast or slow caffeine metabolism genotype.

    Conclusions and Relevance  In this cohort study, small reductions in neonatal anthropometric measurements with increasing caffeine consumption were observed. Findings suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine, are associated with decreased fetal growth.

    Introduction

    Caffeine consumption during pregnancy has been an ongoing topic of debate. As of 2010, the American College of Obstetricians and Gynecologists recommends that pregnant women limit caffeine consumption to less than 200 mg per day.1 However, systematic reviews and meta-analyses have reported that maternal caffeine consumption, even in doses lower than 200 mg, is associated with a higher risk for low birth weight, small for gestational age (SGA), and fetal growth restriction,2,3 suggesting there may be no safe amount of caffeine during pregnancy. However, in 1 meta-analysis,3 4 of 9 studies reported null or contrary results.4-7 These inconsistent associations may have been owing to the reliance of most studies on self-reported measures of caffeine intake.2,3 Coffee varies in its caffeine content based on preparation method, and serving size of caffeinated beverages may vary across respondents.8 Additionally, some studies of caffeine consumption did not control for important confounders such as smoking.9 Further, there are variations in individual caffeine metabolism, such that people with fast metabolism, those with a genetic variant leading to more rapid caffeine metabolism, may be at higher risk for adverse pregnancy outcomes, potentially because of higher exposure to paraxanthine, the primary metabolite in caffeine.10,11

    To our knowledge, no studies have examined the association between caffeine intake and neonatal anthropometric measures beyond weight, length, and head circumference, and few have analyzed plasma concentrations of caffeine and its metabolites or genetic variations in the rate of metabolism associated with neonatal size.4,10,11 Our aim was to examine associations of caffeine consumption, based on both plasma concentrations of caffeine and its metabolites and self-reported caffeinated beverage intake, with multiple measures of neonatal anthropometry. Our secondary aim was to evaluate whether the association between caffeine consumption and neonatal anthropometry may be moderated by genetic variations in fast vs slow caffeine metabolism.

    Methods

    The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies–Singletons (NCT00912132) was designed to prospectively assess fetal growth in a racially/ethnically diverse cohort of pregnant women.12 Nonsmoking women with low-risk pregnancies, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 19.0-29.9, and no history of prepregnancy chronic conditions were enrolled at 12 US clinical sites between 8 and 13 weeks of gestation between 2009 and 2013.12,13 Secondary analysis was completed in 2020. Women were interviewed and provided blood samples. Fetal growth was tracked via ultrasonographic examinations across 6 visits. Of the 2334 women enrolled, we excluded 14 women found ineligible after enrollment, 186 with pregnancies that did not end in a live birth or with unknown birth outcomes, and 33 participants lacking information on plasma caffeine measures or self-reported caffeine consumption, leaving 2101 women and their neonates with self-reported caffeine consumption for analysis. For analyses using measured plasma caffeine and paraxanthine, we excluded 46 additional women who did not consent to have their blood samples used, leaving 2055 participants. Approval for human subjects research was obtained from the NICHD and the institutional review boards of all participating sites, and participants provided written informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

    Neonatal Anthropometric Measures

    Birth weight was abstracted from medical records. Neonatal anthropometric measures were obtained generally within 1 to 3 days after birth (median, 1 day; interquartile range, 1-2 days) by research staff who were trained and credentialed in a standardized manner. Length was measured from the soles of the feet to the top of the head using an electronic infant scale (SECA 416 Infantometer; SECA).14-16 Head circumference was measured by placing a tape around the head anteriorly from the forehead above the eyebrows and posteriorly at the maximum protrusion of the occiput.17,18 Abdominal circumference was measured by placing the measuring tape on the abdomen cephalward of the umbilicus, perpendicular to the trunk’s long mid-axis.19-22 Mid-upper arm circumference and mid-upper thigh circumference were measured on the right side of the body with the tape held perpendicular to the long axis and at the mid-point of the limb. All measurements were taken at least twice. A third measurement was taken if either value was higher than a prespecified technical error rate.23-25 Skin fold measures of abdominal flank, anterior thigh, subscapula, and triceps were taken using calipers. For skin fold outcomes, we excluded 136 neonates from 1 clinical site that used the wrong calipers for measurement. We calculated percent fat mass using a validated formula that combines proportions of neonatal anthropometric measures [0.39055 (neonatal examination weight, g) + 0.0453 (flank skin fold, mm) – 0.03237 (length, cm) + 0.054657].17,26 We examined percent fat mass as an outcome among neonates in whom the formula had been validated—those delivered at term (at least 37 weeks of gestation) or with birth weight greater than or equal to 2000 g (n = 1791). Small for gestational age was defined as birth weight below the tenth percentile for GA using the Duryea reference.27

    Caffeine and Paraxanthine Plasma Concentrations

    Blood was collected at enrollment, processed into plasma, and stored at −80 °C. A detailed description of caffeine and paraxanthine extraction and measurement is available in the eMethods in the Supplement. Briefly, extraction was accomplished by a hybrid solid phase extraction, and quantification of caffeine was performed on a mass spectrometer (AB Sciex 5500; AB Sciex). The detection limit of caffeine through the analytical method was 0.55 ng/mL and for paraxanthine was 0.72 ng/mL and limits of quantitation were 1.85 ng/mL and 2.39 ng/mL, respectively. We assessed total methylxanthine concentrations, defined as the sum of caffeine and paraxanthine.

    Self-reported Caffeine Consumption

    At enrollment participants reported whether they had consumed any caffeinated beverages in the past week (coffee, tea, soda, and energy drinks) and how many cups (8 oz) or cans or bottles (12 oz or 16 oz) consumed per day. Less than 1 serving (cup, can, or bottle) was coded as half a serving. Using USDA guidelines for average caffeine content of each beverage,28 we converted servings per day to milligrams per day by multiplying the number of servings by the mean caffeine content of 8 ounces of coffee (96 mg), 8 ounces of tea (48 mg), 12 ounces of soda (40 mg), or 12 ounces of energy drink (108 mg) to create a summary variable. We calculated total caffeine consumption by summing milligrams per day from all caffeine sources.

    Caffeine Metabolism and CYP1A2 Modification

    Participants were classified as having fast metabolism based on their genotype of AA and CC and slow metabolism based on their genotype of CA for the autosomal single nucleotide variant (SNV) rs762551 in the cytochrome P450 gene (CYP1A2), which regulates caffeine metabolism.10,29-31 DNA was extracted from stored buffy coat specimens collected at enrollment and genotyping was performed using genotyping equipment (Infinium Multi-Ethnic Global BeadChip microarray; Illumina).

    Covariates

    Covariates collected at enrollment included age (years), prepregnancy BMI, race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, or Asian or Pacific Islander), parity (0, 1, or ≥2), married or living with partner (yes/no), educational level (<high school, high school or equivalent, some college or associate’s degree, bachelor’s degree, master’s degree or higher), insurance type (private/managed care or other), and infant sex. For all outcomes except birth weight, we adjusted for number of days elapsed between delivery and neonatal examination.

    Statistical Analysis

    Descriptive analysis using χ2 for categorical variables and t tests for continuous variables were conducted to evaluate demographic differences across caffeine concentration quartiles. Pearson correlation statistics were used to compare plasma caffeine and paraxanthine with self-reported consumption. Caffeine and paraxanthine concentrations represented machine-observed values and were analyzed as quartiles (Q1, Q2, Q3, and Q4) and continuous exposures. Continuous measures were logarithm-transformed, due to skewness, and standardized after adding an appropriate positive value (eg, ln(caffeine +3)) because of negative values produced during the measurement phase. We did not substitute 0 for negative values to minimize bias associated with constraining an exposure to a lower limit.32,33

    Using adjusted generalized linear models, we tested associations between quartiles and continuous measures of caffeine and paraxanthine concentrations and their sum relative to each neonatal outcome. To assess nonlinearity of associations for continuous exposures, we modeled log-transformed exposures as restricted cubic splines with 5 knots. The β coefficients of these models represent the change in neonatal anthropometric measure per SD change in exposure. We assessed risk of SGA using adjusted log-linear regression models.

    Based on the distribution of self-reported caffeine consumption, we categorized participants as consuming no caffeine, consuming 1-50 mg per day, or consuming more than 50 mg per day, fitting models to test associations between self-reported first trimester caffeinated beverage consumption and neonatal anthropometric measures. To ensure that results were not being affected by women who consumed more than 2 cups per day (>200 mg), we performed 2 sensitivity analyses: first, we removed the individuals with the highest consumption (>200 mg/d) from analyses (n = 16), and second, we split the group who consumed more than 50 mg per day into 51 to 100 mg per day (n = 329) and more than 100 mg per day (n = 148).Because of observed race/ethnic differences in fetal growth from the NICHD cohort,13 in separate models, we tested for interactions between race/ethnicity and all caffeine measures for each outcome.

    To test for potential moderation of caffeine metabolism CYP1A2 genotype on the associations between caffeine consumption and neonatal anthropometry, we coded 2-way interaction terms for all caffeine exposures and rate of caffeine metabolism. All interaction models were adjusted for genetic principal components generated from multidimensional scaling analysis to account for population structure. In consideration of allele frequency differences among racial/ethnic groups, we stratified models by race/ethnicity to avoid population-stratification bias in effect estimates. Caffeine metabolism analyses included only women with genetic information to determine genotype of the CYP1A2 gene (n = 1516).

    Final models were not adjusted for plasma cotinine concentrations because it was not significantly associated with caffeine measures and did not change the results. Results were considered statistically significant at P < .05 in 2-tailed tests. All analyses were conducted in SAS version 9.4 (SAS Institute Inc).

    Results

    A total of 2055 participants had a mean (SD) age of 28.3 (5.5) years, mean (SD) body mass index of 23.6 (3.0), and 580 (28.2%) were Hispanic, 562 (27.4%) were White, 518 (25.2%) were Black, and 395 (19.2%) were Asian/Pacific Islander. Delivery occurred at a mean (SD) of 39.2 (1.7) gestational weeks. There were no clear trends in demographic characteristics across quartiles, although women in the highest quartile (Q4) vs lowest quartile (Q1) were older (mean [SD] age: Q4, 29.5 [5.3] years vs Q1, 27.5 [5.3] years; P < .001) and more likely to be non-Hispanic White (No. [%]: Q4, 197 [38.4] vs Q1, 94 [18.3]; P < .001), parous (No. [%] ≥2: Q4, 119 [23.2] vs Q1, 54 [10.5]; P < .001), and married (No. [%]: Q4, 431 [84.2] vs Q1 360 [70.2]; P < .001) (Table 1). Plasma caffeine and paraxanthine concentrations were correlated 84% and detectable for 93% and 89% of the cohort, with median of 157 ng/mL (interquartile range, 28.3-157.2 ng/mL) and 72 ng/mL (interquartile range, 14.8-72.4 ng/mL), respectively. Pearson correlation coefficients for self-reported caffeine consumption and measured caffeine and paraxanthine were r = 0.33 and r = 0.39, respectively. Nearly half (873 of 2055 [41.6%]) of women reported consuming no caffeinated beverages in the first trimester, while 751 of 2055 women (35.7%) reported drinking at least 50 mg (approximately half a cup of coffee per day or less) and 477 of 2055 women (22.7%) reported drinking more than 50 mg per day (15.7% drank 51-100 mg/d; 6.3% drank 101-200 mg/d; 0.7% drank >200 mg/d).

    Caffeine and Paraxanthine Plasma Concentrations

    Neonatal anthropometric measures were negatively associated with quartiles of caffeine and paraxanthine concentrations with significant linear trends observed for birth weight, length, head circumference, and mid-upper arm circumference (P < .05 for trend) (Table 2). For caffeine, women in the highest vs lowest quartile had infants with lower birth weight (β = −84.3 g; 95% CI, −145.9 to −22.6 g; P = .04 for trend), shorter length (β = −0.44 cm; 95% CI, −0.78 to −0.12 cm; P = .04 for trend), and smaller head circumference (β = −0.28 cm; 95% CI, −0.47 to −0.09 cm; P < .001 for trend), mid-upper arm circumference (β = −0.25 cm; 95% CI, −0.41 to −0.09 cm: P = .02 for trend), and mid-upper thigh circumference (β = −0.29 cm; 95% CI, −0.58 to −0.04 cm; P = .07 for trend). Similar negative associations were observed for the highest vs lowest quartile of paraxanthine, with an 83.7-g reduction in birth weight (95% CI, −144.9 to −22.5 g; P = .01), shorter length (β = −0.45 cm; 95% CI, −0.77 to −0.12 cm; P = .01), and smaller head (β = −0.47 cm; 95% CI, −0.47 to −0.09 cm; P = .003), arm (β = -0.23 cm; 95% CI, −0.39 to −0.07 cm; P < .001), and thigh circumference (β = −0.31 cm; 95% CI, −0.57 to −0.05 cm; P = .02). Additionally, the third quartiles of paraxanthine concentrations were associated with shorter length (β = −0.38 cm; 95% CI, −0.70 to −0.06 cm; P = .02), and smaller head circumference (β = −0.34 cm; 95% CI, −0.53 to −0.16; P < .001), and mid-upper arm circumference (β = −0.19; 95% CI, −0.35 to −0.03 cm; P = .02) compared with the first quartile. Similar results were observed when assessing quartiles for the sum, with smaller birth weight (β = −74.4 g; 95% CI, −136.0 to −12.8 g; P = .02), shorter length (β = −0.46 cm; 95% CI, −0.79 to −0.13 cm; P = .01), and smaller head (β = −0.29 cm; 95% CI, −0.48 to −0.10 cm; P = .003), arm (β = −0.25 cm; 95% CI, −0.41 to −0.09 cm; P = 03), and thigh circumference (β = −0.28 cm; 95% CI, −0.54 to −0.02 cm; P = .04) (eTable 1 in the Supplement).

    Our findings for continuous measures were consistent with those of quartile measures, with no evidence for nonlinearity. For each SD increment increase in log caffeine, there was a decrease in birth weight (β = −26.3 g; 95% CI, −47.4 to −5.0 g; P = .004), length (β = −0.14 cm; 95% CI, −0.26 to −0.03 cm; P = .02), and smaller head (β = −0.09 cm; 95% CI, −0.16 to −0.02 cm; P = .01), and arm circumference (β = −0.06 cm; 95% CI, −0.12 to −0.01 cm; P = .04). For log paraxanthine, there was a decrease in birth weight (β = −24.5 g; 95% CI, −45.5 to −3.4 g; P = .01), length (β = −0.18 cm; 95% CI, −0.29 to −0.06 cm; P = .003), and smaller head (β = −0.13 cm; 95% CI, −0.20 to −0.06 cm; P < .001), arm (β = −0.08 cm; 95% CI, −0.13 to −0.02 cm; P = .01), and thigh circumference (β = −0.10 cm; 95% CI, −0.19 to −0.01 cm; P = .04). For each SD increment increase in the log of the sum, there was a decrease in birth weight (β = −25.9 g; 95% CI, −47.1 to −4.8 g; P = .004), length (β = −0.18 cm; 95% CI, −0.30 to −0.06 cm; P = .003), and smaller head (β = −0.13 cm; 95% CI, −0.20 to −0.06 cm; P < .001), arm (β = −0.08 cm; 95% CI, −0.14 to −0.02 cm; P = .01), and thigh circumference (β = −0.10 cm; 95% CI, −0.19 to −0.01 cm; P = .04) (Table 3). Risk of SGA was elevated in the fourth quartile of caffeine (adjusted relative risk = 1.26; 95% CI, 0.83-1.91) and paraxanthine (adjusted relative risk = 1.31; 95% CI, 0.85-2.00) (Table 4). There were no significant interactions between race and any measure of caffeine consumption (eTable 2 in the Supplement).

    Self-reported Consumption

    Coffee and soda were the primary sources of caffeine consumption, with 35% of participants (736 of 2101) consuming coffee and 41% (870 of 2101) consuming soda. Analyses were conducted based on reports at the enrollment visit, but caffeinated beverage intake was reported across visits and remained consistent for 98% of women in the second and third trimesters. Compared with women who reported no caffeinated beverage intake, women who reported drinking at least 50 mg per day had neonates with smaller subscapular skin folds (β = −0.14 mm; 95% CI, −0.27 to −0.01 mm) and women who reported drinking more than 50 mg per day had neonates with lower birth weight (β = −66 g; 95% CI, −121 to −10 g) and smaller mid-upper arm circumference (β = −0.17 cm; 95% CI, −0.31 to −0.02 cm), mid-upper thigh circumference (β = −0.32 cm; 95% CI, −0.55 to −0.09 cm), and anterior thigh skin fold (β = −0.24 mm; −0.47 to −0.01 mm) (Table 5). Results were robust in sensitivity analysis.

    Caffeine Metabolism

    In testing interactions between metabolism rate and caffeine or paraxanthine quartiles, there were no significant interactions for any neonatal anthropometric measure indicating that the association between caffeine concentrations and neonatal anthropometry did not vary by rate of caffeine metabolism. Results were consistent for self-reported measures.

    Discussion

    In this cohort study of pregnant women with low caffeine consumption, even small increases in plasma caffeine concentrations and its major metabolite paraxanthine, were associated with lower birth weight, finding that smaller size was manifested by shorter length, and smaller head, arm and thigh circumferences at birth. The decreases in bone and muscle measures, but not skin folds and fat mass, may indicate decreases in lean tissue as caffeine consumption increases. Results were consistent with self-reported caffeine consumption, in which consumption of at least 50 mg (approximately half a cup of coffee) per day was associated with lower birth weight and smaller neonatal anthropometric measurements, even when excluding individuals who consumed higher amounts (>200 mg). Associations between caffeine and neonatal anthropometric measures did not vary by fast or slow caffeine metabolism.

    Our findings of decreased birth weight and length associated with both plasma caffeine and paraxanthine concentrations and caffeinated beverage intake are consistent with meta-analyses that have reported a dose-response association between self-reported maternal caffeine consumption and the risk of low birth weight, SGA, and fetal growth restriction,2,3,34 although associations with measured caffeine have not previously been established. Pooled statistics in these analyses demonstrated a graded risk in low birth weight that increases with each additional cup of coffee (100 mg) consumed per day, suggesting that even low amounts of caffeine consumption during pregnancy are associated with smaller offspring birth size. Similarly, we observed no threshold effect for caffeine consumption, as shown by associations between caffeine biomarkers and anthropometric measurements, and the finding that even low consumption of caffeinated beverages was associated with less lean tissue, which may have long-term implications for cardiometabolic risk.35 To our knowledge, few studies have explored caffeine consumption in association with neonatal anthropometric measures beyond birth weight and length.10,36,37 Our results are consistent with 2 studies that additionally explored head circumference,10,36 although our sample was larger, and our detailed measures specifically characterized changes in lean and fat tissue. In addition, we observed these associations in a cohort of pregnant women with low mean caffeine consumption (36 mg/d). Our findings are in contrast to null associations with neonatal weight, length, and head circumference observed in another study conducted in a low-consumption sample,37 however, that study included only 100 women, possibly lacking power to detect an association.

    Other studies assessing caffeinated beverage intake instead of measured caffeine and paraxanthine concentrations have suggested increased risk of negative growth outcomes such as SGA and fetal growth restriction only after consumption of 200 to 300 mg per day.4,38 Consistent with this finding, we observed higher risk for SGA in the fourth quartile of measured caffeine and paraxanthine concentrations, although results were not significant, likely because of low overall consumption in the sample. However, SGA is an extreme of birth weight, and does not describe incremental changes that may signal a negative association between caffeine and neonatal size. When evaluating outcomes continuously, a 2018 study noted linear decreases in birth weight, length, and head circumference with increasing self-reported caffeine consumption, as observed in our study.36 We were unable to directly calculate plasma caffeine or paraxanthine concentrations to the amount of caffeine consumed. However, it is estimated that among pregnant women in their first trimester, consuming 55 mg of caffeine translates to a mean blood caffeine concentration of 1859 ng/mL an hour after consumption.39 In the context of our study, when comparing the fourth with the first caffeine quartiles, a 630 ng/mL increase in caffeine concentration translated to an 84 g reduction in birth weight and a 0.44 cm decrease in length. Thus, our results indicate that even small increases in caffeine consumption in the first trimester may translate to reductions in neonatal anthropometric measures, and our findings were robust in multiple analyses.

    The long-term implications of our findings are unclear, considering the relatively small estimates we observed. Caffeine metabolism slows throughout pregnancy.39 Because the fetus lacks CYP1A2 enzymes for metabolism, caffeine and paraxanthine accumulate in fetal tissues.40 Caffeine is hypothesized to alter fetal growth via disruption of neuroendocrine processes that cause uteroplacental vasoconstriction, hinder organ development, and permanently alter the stress response.40 In the long term, these disruptions may put offspring at higher risk for rapid weight gain after birth, childhood obesity, and chronic disease.41,42 Even low maternal caffeine intake (>50 mg/d) is associated with higher risk of excess growth in infancy and overweight in early childhood and altered fat deposition that may put children of caffeine consumers at higher risk of later cardiometabolic disease.41,43

    Although evidence supports high interindividual variation in the rate of caffeine metabolism,10,11,44 we did not observe a modifying effect of caffeine metabolism. However, this null finding may, in part, be owing to the low level of consumption in our sample. To date, only 1 study has examined caffeine metabolism genotypes in the context of pregnancy, finding that differences in associations between caffeine and neonatal anthropometry only differed by metabolism rate among high-consumption groups (≥300 mg/d).10 Additionally, our sample was racially/ethnically diverse, which necessitated further stratification by race, limiting the power to detect a small effect. Although we used a validated SNV to define fast and slow metabolism, there are likely multiple genes involved in caffeine metabolism, and in a low-consumption sample, a single SNV may not be a sensitive indicator of metabolism alone.

    Strengths and Limitations

    A major strength of our study was the ability to investigate caffeine intake from multiple measures including plasma caffeine and paraxanthine concentrations, self-reported caffeine consumption, and genetic information on caffeine metabolism. Unlike previous studies which relied mostly on coffee consumption,38 our self-reported measure included caffeinated coffee, tea, soda, and energy drinks. Another strength is the numerous, rigorously collected anthropometric measures, which allowed us to investigate associations with neonatal lean and fat measures. In addition, by limiting our sample to nonsmokers without chronic disease, we reduced unmeasured confounding in our analyses.

    This study has limitations. Similar to other studies assessing first trimester consumption,45 there was low correlation between self-reported caffeinated beverage intake and plasma caffeine and paraxanthine in our sample, possibly because of variability in caffeine amounts from beverage intake,8 differential rates of metabolism, and lack of information on timing of last consumption. By using biomarker data, we overcame many of these limitations and recorded caffeine exposure from consuming certain foods, such as chocolate and decaffeinated beverages, which may contain small amounts of caffeine. We measured plasma caffeine and paraxanthine once in pregnancy, although it should be noted that self-reported caffeine remained constant for 98% of the sample in the second and third trimesters. This finding is consistent with other caffeine studies that found stable reported consumption across trimesters,4,5 and little variability in results based on timing of exposure.4 Thus, measuring caffeine in the first trimester may be a good proxy of consumption throughout pregnancy, but evaluation of caffeine biomarker changes across trimesters may be warranted in future studies.

    Conclusions

    In this cohort study, we observed small reductions in neonatal anthropometric measurements with increasing caffeine consumption. Our results suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine1 may be associated with decreased fetal growth.

    Back to top
    Article Information

    Accepted for Publication: February 4, 2021.

    Published: March 25, 2021. doi:10.1001/jamanetworkopen.2021.3238

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Gleason JL et al. JAMA Network Open.

    Corresponding Author: Katherine L. Grantz, MD, MS, Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Dr, MSC 7004, Bethesda, MD 20892 (katherine.grantz@nih.gov).

    Author Contributions: Drs Gleason and Sundaram had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Gleason, Buck Louis, Kannan, Grantz.

    Acquisition, analysis, or interpretation of data: Gleason, Tekola-Ayele, Sundaram, Hinkle, Vafai, Gerlanc, Amyx, Bever, Smarr, Robinson, Kannan.

    Drafting of the manuscript: Gleason, Sundaram.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Gleason, Sundaram, Hinkle, Gerlanc.

    Obtained funding: Buck Louis.

    Administrative, technical, or material support: Buck Louis.

    Supervision: Grantz.

    Conflict of Interest Disclosures: Dr Gerlanc reported being an employee of The Prospective Group, Arlington, Virginia, contracted to NICHD to provide statistical support during the conduct of the study. No other disclosures were reported.

    Funding/Support: Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C; HHSN275200800012C; HHSN275200800028C; HHSN275201000009C; and HHSN27500008. Additional support for genotyping was obtained from the NIH Office of the Director). The study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

    Role of the Funder/Sponsor: The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: Drs Tekola-Ayele, Sundaram, Hinkle, and Grantz are employees of the US federal government.

    Meeting Presentation: This paper was presented as a poster at the Annual Meeting of the Society for Pediatric and Perinatal Epidemiologic Research; June 11, 2018; Baltimore, Maryland.

    References
    1.
    ACOG Committee.  ACOG Committee Opinion No. 462: moderate caffeine consumption during pregnancy.   Obstet Gynecol. 2010;116(2 Pt 1):467-468.PubMedGoogle Scholar
    2.
    Rhee  J, Kim  R, Kim  Y,  et al.  Maternal caffeine consumption during pregnancy and risk of low birth weight: a dose-response meta-analysis of observational studies.   PLoS One. 2015;10(7):e0132334. doi:10.1371/journal.pone.0132334 PubMedGoogle Scholar
    3.
    Chen  L-W, Wu  Y, Neelakantan  N, Chong  MF-F, Pan  A, van Dam  RM.  Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose-response meta-analysis.   BMC Med. 2014;12(1):174. doi:10.1186/s12916-014-0174-6 PubMedGoogle ScholarCrossref
    4.
    Group  C; CARE Study Group.  Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study.   BMJ. 2008;337:a2332. doi:10.1136/bmj.a2332 PubMedGoogle ScholarCrossref
    5.
    Bakker  R, Steegers  EA, Obradov  A, Raat  H, Hofman  A, Jaddoe  VW.  Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: the Generation R Study.   Am J Clin Nutr. 2010;91(6):1691-1698. doi:10.3945/ajcn.2009.28792 PubMedGoogle ScholarCrossref
    6.
    Grosso  LM, Rosenberg  KD, Belanger  K, Saftlas  AF, Leaderer  B, Bracken  MB.  Maternal caffeine intake and intrauterine growth retardation.   Epidemiology. 2001;12(4):447-455. doi:10.1097/00001648-200107000-00015 PubMedGoogle ScholarCrossref
    7.
    Bracken  MB, Triche  EW, Belanger  K, Hellenbrand  K, Leaderer  BP.  Association of maternal caffeine consumption with decrements in fetal growth.   Am J Epidemiol. 2003;157(5):456-466. doi:10.1093/aje/kwf220 PubMedGoogle ScholarCrossref
    8.
    Poole  R, Ewings  S, Parkes  J, Fallowfield  JA, Roderick  P.  Misclassification of coffee consumption data and the development of a standardised coffee unit measure.   BMJ Nutr Prev Health. 2019;2(1):11-19. doi:10.1136/bmjnph-2018-000013 PubMedGoogle ScholarCrossref
    9.
    de Medeiros  TS  Jr, Bernardi  JR, de Brito  ML, Bosa  VL, Goldani  MZ, da Silva  CH.  Caffeine intake during pregnancy in different intrauterine environments and its association with infant anthropometric measurements at 3 and 6 months of age.   Matern Child Health J. 2017;21(6):1297-1307. doi:10.1007/s10995-016-2230-7 PubMedGoogle ScholarCrossref
    10.
    Sasaki  S, Limpar  M, Sata  F, Kobayashi  S, Kishi  R.  Interaction between maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido study.   Pediatr Res. 2017;82(1):19-28. doi:10.1038/pr.2017.70 PubMedGoogle ScholarCrossref
    11.
    Grosso  LM, Triche  EW, Belanger  K, Benowitz  NL, Holford  TR, Bracken  MB.  Caffeine metabolites in umbilical cord blood, cytochrome P-450 1A2 activity, and intrauterine growth restriction.   Am J Epidemiol. 2006;163(11):1035-1041. doi:10.1093/aje/kwj125 PubMedGoogle ScholarCrossref
    12.
    Grewal  J, Grantz  KL, Zhang  C,  et al.  Cohort profile: NICHD Fetal Growth Studies-Singletons and Twins.   Int J Epidemiol. 2018;47(1):25-25l. doi:10.1093/ije/dyx161 PubMedGoogle ScholarCrossref
    13.
    Buck Louis  GM, Grewal  J, Albert  PS,  et al.  Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies.   Am J Obstet Gynecol. 2015;213(4):449.e1-449.e41. doi:10.1016/j.ajog.2015.08.032 PubMedGoogle ScholarCrossref
    14.
    Doull  IJ, McCaughey  ES, Bailey  BJ, Betts  PR.  Reliability of infant length measurement.   Arch Dis Child. 1995;72(6):520-521. doi:10.1136/adc.72.6.520 PubMedGoogle ScholarCrossref
    15.
    Shinwell  ES, Shlomo  M.  Measured length of normal term infants changes over the first two days of life.   J Pediatr Endocrinol Metab. 2003;16(4):537-540. doi:10.1515/JPEM.2003.16.4.537 PubMedGoogle ScholarCrossref
    16.
    Pereira-Da-Silva  L, Bergmans  KI, van Kerkhoven  LA, Leal  F, Virella  D, Videira-Amaral  JM.  Reducing discomfort while measuring crown-heel length in neonates.   Acta Paediatr. 2006;95(6):742-746. doi:10.1080/08035250500516623 PubMedGoogle ScholarCrossref
    17.
    Catalano  PM, Thomas  AJ, Avallone  DA, Amini  SB.  Anthropometric estimation of neonatal body composition.   Am J Obstet Gynecol. 1995;173(4):1176-1181. doi:10.1016/0002-9378(95)91348-3 PubMedGoogle ScholarCrossref
    18.
    National Health and Nutrition Examination Survey. Anthropometry Procedures Manual. Published January 2007. Accessed February 23, 2021. https://www.cdc.gov/nchs/data/nhanes/nhanes_07_08/manual_an.pdf
    19.
    Williams  AM, Brain  JL.  The normal position of the umbilicus in the newborn: an aid to improving the cosmetic result in exomphalos major.   J Pediatr Surg. 2001;36(7):1045-1046. doi:10.1053/jpsu.2001.24737 PubMedGoogle ScholarCrossref
    20.
    Stetzer  BP, Thomas  A, Amini  SB, Catalano  PM.  Neonatal anthropometric measurements to predict birth weight by ultrasound.   J Perinatol. 2002;22(5):397-402. doi:10.1038/sj.jp.7210754 PubMedGoogle ScholarCrossref
    21.
    Fok  TF, Hon  KL, Wong  E,  et al; Hong Kong Neonatal Measurements Working Group.  Trunk anthropometry of Hong Kong Chinese infants.   Early Hum Dev. 2005;81(9):781-790. doi:10.1016/j.earlhumdev.2005.06.002 PubMedGoogle ScholarCrossref
    22.
    Rodríguez  G, Samper  MP, Ventura  P, Pérez-González  JM.  Sex-specific charts for abdominal circumference in term and near-term Caucasian newborns.   J Perinat Med. 2008;36(6):527-530. doi:10.1515/JPM.2008.077 PubMedGoogle ScholarCrossref
    23.
    de Onis  M, Onyango  AW, Van den Broeck  J, Chumlea  WC, Martorell  R.  Measurement and standardization protocols for anthropometry used in the construction of a new international growth reference.   Food Nutr Bull. 2004;25(1)(suppl):S27-S36. doi:10.1177/15648265040251S105 PubMedGoogle ScholarCrossref
    24.
    Johnson  TS, Engstrom  JL, Gelhar  DK.  Intra- and interexaminer reliability of anthropometric measurements of term infants.   J Pediatr Gastroenterol Nutr. 1997;24(5):497-505. doi:10.1097/00005176-199705000-00001 PubMedGoogle ScholarCrossref
    25.
    Ulijaszek  SJ, Kerr  DA.  Anthropometric measurement error and the assessment of nutritional status.   Br J Nutr. 1999;82(3):165-177. doi:10.1017/S0007114599001348 PubMedGoogle ScholarCrossref
    26.
    Catalano  PM, Mele  L, Landon  MB,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.  Inadequate weight gain in overweight and obese pregnant women: what is the effect on fetal growth?   Am J Obstet Gynecol. 2014;211(2):137.e1-137.e7. doi:10.1016/j.ajog.2014.02.004 PubMedGoogle ScholarCrossref
    27.
    Duryea  EL, Hawkins  JS, McIntire  DD, Casey  BM, Leveno  KJ.  A revised birth weight reference for the United States.   Obstet Gynecol. 2014;124(1):16-22. doi:10.1097/AOG.0000000000000345 PubMedGoogle ScholarCrossref
    28.
    US Department of Agriculture ARS. FoodData Central. Published 2019. Accessed February 29, 2020. https://fdc.nal.usda.gov/
    29.
    Ghotbi  R, Christensen  M, Roh  HK, Ingelman-Sundberg  M, Aklillu  E, Bertilsson  L.  Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans.   Eur J Clin Pharmacol. 2007;63(6):537-546. doi:10.1007/s00228-007-0288-2 PubMedGoogle ScholarCrossref
    30.
    Han  XM, Ouyang  DS, Chen  XP,  et al.  Inducibility of CYP1A2 by omeprazole in vivo related to the genetic polymorphism of CYP1A2.   Br J Clin Pharmacol. 2002;54(5):540-543. doi:10.1046/j.1365-2125.2002.01686.x PubMedGoogle ScholarCrossref
    31.
    Sachse  C, Brockmöller  J, Bauer  S, Roots  I.  Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine.   Br J Clin Pharmacol. 1999;47(4):445-449. doi:10.1046/j.1365-2125.1999.00898.x PubMedGoogle ScholarCrossref
    32.
    Richardson  DB, Ciampi  A.  Effects of exposure measurement error when an exposure variable is constrained by a lower limit.   Am J Epidemiol. 2003;157(4):355-363. doi:10.1093/aje/kwf217 PubMedGoogle ScholarCrossref
    33.
    Schisterman  EF, Vexler  A, Whitcomb  BW, Liu  A.  The limitations due to exposure detection limits for regression models.   Am J Epidemiol. 2006;163(4):374-383. doi:10.1093/aje/kwj039 PubMedGoogle ScholarCrossref
    34.
    Jin  F, Qiao  C.  Association of maternal caffeine intake during pregnancy with low birth weight, childhood overweight, and obesity: a meta-analysis of cohort studies.   Int J Obes (Lond). 2021;45(2):279-287. doi:10.1038/s41366-020-0617-4PubMedGoogle ScholarCrossref
    35.
    Brown  LD.  Endocrine regulation of fetal skeletal muscle growth: impact on future metabolic health.   J Endocrinol. 2014;221(2):R13-R29. doi:10.1530/JOE-13-0567 PubMedGoogle ScholarCrossref
    36.
    Chen  LW, Fitzgerald  R, Murrin  CM, Mehegan  J, Kelleher  CC, Phillips  CM; Lifeways Cross Generation Cohort Study.  Associations of maternal caffeine intake with birth outcomes: results from the Lifeways Cross Generation Cohort Study.   Am J Clin Nutr. 2018;108(6):1301-1308. doi:10.1093/ajcn/nqy219 PubMedGoogle ScholarCrossref
    37.
    Wierzejska  R, Jarosz  M, Wojda  B.  Caffeine intake during pregnancy and neonatal anthropometric parameters.   Nutrients. 2019;11(4):E806. doi:10.3390/nu11040806 PubMedGoogle Scholar
    38.
    Hoyt  AT, Browne  M, Richardson  S, Romitti  P, Druschel  C; National Birth Defects Prevention Study.  Maternal caffeine consumption and small for gestational age births: results from a population-based case-control study.   Matern Child Health J. 2014;18(6):1540-1551. doi:10.1007/s10995-013-1397-4 PubMedGoogle ScholarCrossref
    39.
    Yu  T, Campbell  SC, Stockmann  C,  et al.  Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites.   J Clin Pharmacol. 2016;56(5):590-596. doi:10.1002/jcph.632 PubMedGoogle ScholarCrossref
    40.
    Zhang  C, Xu  D, Luo  H,  et al.  Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration.   Toxicology. 2014;325:74-84. doi:10.1016/j.tox.2014.08.015 PubMedGoogle ScholarCrossref
    41.
    Papadopoulou  E, Botton  J, Brantsæter  A-L,  et al.  Maternal caffeine intake during pregnancy and childhood growth and overweight: results from a large Norwegian prospective observational cohort study.   BMJ Open. 2018;8(3):e018895. doi:10.1136/bmjopen-2017-018895 PubMedGoogle Scholar
    42.
    Reynolds  RM.  Corticosteroid-mediated programming and the pathogenesis of obesity and diabetes.   J Steroid Biochem Mol Biol. 2010;122(1-3):3-9. doi:10.1016/j.jsbmb.2010.01.009 PubMedGoogle ScholarCrossref
    43.
    Voerman  E, Jaddoe  VW, Hulst  ME, Oei  EH, Gaillard  R.  Associations of maternal caffeine intake during pregnancy with abdominal and liver fat deposition in childhood.   Pediatr Obes. 2020;15(5):e12607. doi:10.1111/ijpo.12607 PubMedGoogle Scholar
    44.
    Nehlig  A.  Interindividual differences in caffeine metabolism and factors driving consumption.   Pharmacol Rev. 2018;70(2):384-411. doi:10.1124/pr.117.014407 PubMedGoogle ScholarCrossref
    45.
    Grosso  LM, Triche  E, Benowitz  NL, Bracken  MB.  Prenatal caffeine assessment: fetal and maternal biomarkers or self-reported intake?   Ann Epidemiol. 2008;18(3):172-178. doi:10.1016/j.annepidem.2007.11.005 PubMedGoogle ScholarCrossref
    ×