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Obesity (Silver Spring). Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Obesity (Silver Spring). 2016 June ; 24(6): 1320–1327. doi:10.1002/oby.21484.

Maternal inflammation during pregnancy and childhood adiposity Romy Gaillard, PhD1,2, Sheryl L. Rifas-Shiman, MPH3, Wei Perng, PhD4, Emily Oken, MD, MPH3,5, and Matthew W. Gillman, MD, SM3,5

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1The

Generation R Study Group, Erasmus Medical Center, Rotterdam, the Netherlands of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands 3Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts 4Department of Nutritional Sciences, Department of Epidemiology, University of Michigan , School of Public Health, Ann Arbor, MI 5Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 2Department

Abstract Objective—Maternal prepregnancy obesity is associated with offspring obesity. Underlying mechanisms may involve a maternal-obesity-mediated pro-inflammatory state during pregnancy. Maternal C-reactive protein (CRP)-level during pregnancy is a biomarker of low-grade systemic inflammation.

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Methods—Among 1116 mother-child pairs, we examined associations of maternal second trimester CRP-plasma-level, measured by high-sensitivity-CRP-arrays, with mid-childhood DXA fat-mass-index (FMI), trunk-fat-mass-index (trunkFMI), fat-free-mass-index (FFMI), and earlyand mid-childhood BMI-z and waist circumference (WC). Main analyses were adjusted for maternal socio-demographic and lifestyle-related characteristics, gestational age at blood draw, child’s age, sex.

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Results—Higher maternal CRP-level was associated with higher mid-childhood FMI and trunkFMI (adjusted difference: 0.15 kg/m2 [95%CI: 0.01, 0.29] [p-value=0.04] and 0.06 kg/m2 [95%CI: 0.00, 0.12] [p-value=0.06], per SD increment in maternal CRP, respectively), but not FFMI. Higher maternal CRP-level was associated with higher early- and mid-childhood BMI-z and WC in the basic models [p-value10 days. Based on U.S. national natality data, we determined sex-specific birth weight for gestational age z scores(23). As described in detail previously, to identify mothers who developed gestational hypertension or preeclampsia, we reviewed outpatient charts for blood pressure and urine protein results, and additionally reviewed inpatient hospital charts only for women who had a diagnosis or discharge code indicating preeclampsia or gestational hypertension and who did not already meet criteria for the same diagnosis based upon our review of outpatient charts (24).

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We obtained data on gestational diabetes (GDM) from the clinical laboratory and diagnosis records, which we described in detail previously (25). Briefly, obstetric clinicians routinely screened all women for GDM at 26–28 weeks of gestation with a nonfasting oral glucose challenge test (GCT), in which venous blood was sampled 1-h after a 50-g oral glucose load. If the blood glucose exceeded 140 mg/dL, the clinician referred the woman for a fasting 3-h 100-g oral glucose tolerance test (OGTT). We categorized women into 4 categories: GDM when women had two or more abnormal values on the OGTT; impaired glucose tolerance when women had one abnormal value on the OGTT; women with an abnormal GCT but a normal OGTT; and women with a normal glucose tolerance (25). Statistical analysis

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First, we explored bivariate associations of maternal and fetal characteristics with second trimester maternal CRP-level using linear regression models. Second, we examined the associations of maternal CRP-level with early-childhood and mid-childhood adiposity outcomes using linear regression models. We constructed 4 different models to examine these associations: 1) a basic model adjusted for gestational age at maternal CRP measurement, child sex and age at outcome measurement; 2) a confounder model, which was additionally adjusted for maternal age, pre-pregnancy BMI, race/ethnicity, educational level, parity, smoking during pregnancy and total calorie intake during pregnancy; 3) mediator models, which additionally included maternal pregnancy complications and birth characteristics as potential intermediates; 4) a fully adjusted model including all covariates. Similar results were found when we used maternal BMI at CRP measurement in the second trimester instead of maternal prepregnancy BMI (results not shown). Additional adjustment for maternal total gestational weight gain only marginally changed the observed effect estimates (results not shown). For all analyses, we constructed internal z-scores of maternal CRP to analyse the continuous associations with early- and mid-childhood adiposity outcomes. We examined potential interactions between maternal CRP-level and offspring sex, but since no significant interactions were present, no further stratified analyses were

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performed. Sensitivity analyses were performed among women with a normal glucose tolerance status only. Missing data of variables were imputed using multiple imputations. We generated 50 imputed data sets, and results were computed by appropriately combining these results. We used all 2128 Project Viva subjects in the imputation process, but the analysis sample included only the 1116 participants with maternal mid-pregnancy blood available and earlyor mid-childhood in-person visits. For early-childhood outcomes, we included 1043 participants with an early-childhood in-person visit and for mid-childhood outcomes, we included 874 participants with a mid-childhood in-person visit. As compared to the complete case analysis, the effect estimates only changed slightly after using multiple imputations to deal with the missing values (results not shown). We conducted all of the analyses using SAS version 9.3 (SAS Institute, Inc, Cary, North Carolina).

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RESULTS Maternal and childhood characteristics and CRP-level Characteristics of the included mothers and children are given in Table 1. Median (IQR) maternal level of CRP was 1.2 mg/l (0.6, 2.1). Mean (SD) BMI-z was 0.43 (1.04) and WC 51.3 cm (3.5) in early-childhood. Mean (SD) mid-childhood FMI was 4.3 kg/m2 (1.8) , trunkFMI 1.4 kg/m2 (0.8), FFMI 13.0 kg/m2 (1.4), BMI-z 0.35 (0.98) and WC 59.6 cm (7.7).

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Bivariate associations between maternal and fetal characteristics and second trimester maternal CRP-level are given in Table 2. Second trimester maternal CRP-level was higher among overweight and obese women and among women with gestational diabetes (difference in maternal CRP-level for overweight and obese women and women with gestational diabetes: 0.51 mg/L [95% CI: 0.29, 0.73], 1.02 mg/L [95% CI: 0.78, 1.27] and 0.55 mg/L [95% CI: 0.07, 1.02], as compared to normal weight women and women without gestational diabetes, respectively). No consistent associations of other maternal and fetal characteristics with maternal second trimester CRP-level were present. Maternal inflammatory markers and early- and mid-childhood body composition

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Table 3 shows the associations of maternal second trimester CRP-level with detailed midchildhood body fat mass measures measured by DXA, and the role of potential confounders and intermediates. A higher maternal second trimester CRP-level was associated with a higher childhood fat mass index and trunk fat mass index in the basic model (difference in FMI and trunkFMI: 0.30 kg/m2 [95% CI: 0.16, 0.44] and 0.12 kg/m2 [95% CI: 0.06, 0.18], per SD increment in maternal CRP-level, respectively). Additional adjustment for maternal socio-demographic and lifestyle-related characteristics attenuated these associations to 0.15 kg/m2 [95% CI: 0.01, 0.29] and 0.06 kg/m2 [95% CI: 0.00, 0.12], respectively. Adjustment for maternal pregnancy complications and birth characteristics did not further attenuate these associations. A higher maternal second trimester CRP-level was also associated with a higher mid-childhood fat free mass index in the basic model (difference in FFMI: 0.13 kg/m2 [95% CI: 0.03, 0.24] per SD increment in maternal CRP-level, respectively), but this

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association was fully explained by maternal socio-demographic and lifestyle-related characteristics (difference in FFMI: 0.01 kg/m2 [95% CI: −0.10, 0.12] per SD increment in maternal CRP-level, respectively). Table 4 shows the associations of maternal second trimester CRP-level with early- and midchildhood BMI-z and waist circumference. In the basic model, higher maternal second trimester plasma CRP-level was associated with higher early- and mid-childhood BMI-z and waist circumference (difference in early-childhood and mid-childhood BMI-z and WC: 0.12 [95% CI: 0.05, 0.20], 0.25 cm [95% CI: 0.00, 0.50] and 0.16 [95% CI:0.08, 0.23], 1.02 cm [95% CI: 0.44, 1.60], per SD increment in maternal CRP-level, respectively).

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Additional adjustment for maternal socio-demographic and lifestyle-related characteristics attenuated these associations by approximately 58%. The largest reduction in the effect estimates was due to adjustment for maternal prepregnancy BMI. Thus after adjustment, positive associations of maternal CRP-level with early- and mid-childhood BMI-z and waist circumference were present (difference in early-childhood and mid-childhood BMI-z and WC: (0.05 [95% CI: −0.03, 0.13], 0.10 cm [95% CI: −0.17, 0.37] and 0.07 [95% CI:−0.01, 0.14], 0.34 cm [95% CI:−0.25, 0.94], per SD increment in maternal CRP-level, respectively), although these associations did not reach statistical significance. In the intermediate and full models, we found that the associations of maternal second trimester CRP-level with early- and mid-childhood BMI-z and waist circumference were not attenuated by maternal pregnancy complications or birth characteristics. We observed similar associations when we restricted the analyses to women with a normal glucose tolerance status only (results not shown).

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DISCUSSION In this cohort study of pregnant women and their children, we observed that a higher maternal second trimester plasma CRP-level, a marker of maternal low-grade systemic inflammation, was associated with a higher risk of childhood overall adiposity and central adiposity. Interpretation of main findings

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Maternal prepregnancy obesity is associated with increased risks of obesity and adverse cardio-metabolic outcomes in the offspring (1). The mechanisms underlying these associations remain unclear, but may involve an increased maternal obesity mediated proinflammatory state during pregnancy (2). In non-pregnant state, obesity is associated with an increased inflammatory response, which is characterized by abnormal production of adipokine and activation of pro-inflammatory signalling pathways (26). This leads to altered plasma levels of multiple inflammatory markers, such as CRP, TNF- à and IL-6 among obese individuals (26). This increased inflammatory state related to obesity may play a role in the development of atherosclerosis, diabetes and cardiovascular disease (27, 28, 29). During pregnancy, maternal obesity probably also leads to an increased pro-inflammatory state, which may adversely affect placental and fetal development, and long-term offspring cardio-metabolic health outcomes(5, 7, 8, 9).

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We examined the associations of maternal CRP-level, measured in second trimester of pregnancy, with detailed offspring adiposity measures. CRP is a non-specific marker of lowgrade systemic inflammation and a downstream marker of pro-inflammatory cytokines, as production of CRP is stimulated by pro-inflammatory cytokines, such as IL-6 and TNF- à (14). In addition, CRP itself has pro-inflammatory properties and adversely affects endothelial function(14). A Mendelian randomization study, a study design that uses a genetic variant robustly associated with the exposure of interest and not affected by confounding as an instrumental variable, among 21_836 participants showed a causal association of increased BMI with higher CRP levels(30). Among pregnant women, similar findings are reported. A cross-sectional study among 80 pregnant women showed that maternal obesity was associated with increased CRP-levels in the second trimester of pregnancy(31). A longitudinal study performed by Friis et al. among 240 pregnant women showed that maternal obesity was associated with increased CRP-levels during the first half of pregnancy, but differences in CRP-levels between maternal BMI-categories were no longer present towards the end of pregnancy(32). In line with these previous findings, we observed that maternal prepregnancy overweight and obesity were associated with a higher plasma level of maternal second trimester CRP.

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Increased maternal CRP-levels during pregnancy are associated with an increased risk of adverse birth outcomes. Previously, we have shown among a nested-case control study within Project Viva, that a higher maternal CRP-level in the second trimester of pregnancy was associated with an increased risk of preterm delivery(19). A study among 6061 pregnant women showed that a higher level of maternal CRP was associated with fetal growth restriction(33). Both preterm birth and fetal growth restriction are risk factors for the development of increased fat mass levels in later life (34). Few studies have examined the associations of maternal CRP-level or other inflammatory markers during pregnancy with long-term detailed adiposity outcomes in the offspring. A study among 71 singleton white women with normal glucose tolerance showed no correlations of maternal IL-6 , IL-1b and TNF- à levels, measured at 28 weeks and 37 weeks of gestation, with fetal adiposity measures or birth weight (35). A study among 18 multi-ethnic women performed in the US showed that higher maternal IL-6, measured at delivery, correlated with higher neonatal fat mass (12). In a recent study among 439 Danish mother-offspring pairs, Danielsen et al did not find associations of maternal third trimester CRP, TNF-à, IL-6, and IL-1b with offspring BMI, waist circumference, blood pressure and metabolic measures at the age of 20 years (13).

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We observed that a higher maternal CRP-level in the second trimester was associated with increased total body fat mass and truncal fat mass in the offspring. These associations were independent of maternal prepregnancy BMI and not explained by the development of maternal pregnancy complications, including gestational diabetes and gestational hypertensive disorders, or gestational age and weight at birth. A higher second trimester maternal CRP-level was also associated with slightly higher early- and mid-childhood BMI and waist circumference, but these associations attenuated after adjustment for maternal socio-demographic and lifestyle-related characteristics, especially maternal prepregnancy BMI. Differences between our findings and those of Danielsen et al. may be due to differences in timing of maternal inflammatory marker measurement (13). In early Obesity (Silver Spring). Author manuscript; available in PMC 2017 June 01.

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pregnancy, an increased maternal inflammatory state may be more strongly present than later in pregnancy, as later pregnancy is typically characterized by a physiological antiinflammatory state. Accordingly, average CRP-levels tend to be higher in the second trimester of pregnancy than in the third trimester(36). Friis et al. also showed no differences in CRP-level between maternal BMI-categories towards the end of pregnancy (32). Also, differences in study populations and body composition measurements may partly explain these different findings, as we observed the strongest associations with detailed childhood fat mass measures.

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The observed effect estimates for the associations of maternal second trimester CRP-level with childhood overall and central adiposity levels were in the order of a 1/10 SD difference in childhood adiposity levels per SD increment in maternal CRP. Thus, these differences are relatively small, compared to previous reported effect estimates for associations of maternal prepregnancy BMI with offspring adiposity outcomes (1). However, our findings are of importance on a population level and from an etiological perspective, as they provide a potential underlying causal mechanism by which maternal prepregnancy obesity may influence adiposity levels in offspring. The potential mechanisms that explain how a maternal pro-inflammatory state during pregnancy may lead to higher adiposity levels in the offspring are not known. Maternal inflammatory status may affect placental vascular function and inflammatory processes in the placenta, which may lead to suboptimal placental development and alterations in placental structure and function (7, 9, 37). Also, epigenetic influences on placental genes induced by an increased maternal inflammatory state may lead to a placental lipotoxic environment and increased placental inflammation, which negatively affects placental function (8, 38, 39). Suboptimal placental development and function may affect fetal nutrient supply and lead to fetal developmental adaptations in early life, which may predispose to a higher risk of obesity in later life (34). Increased maternal and placental inflammatory processes may also lead to inflammation-related maternal insulin resistance, which may subsequently lead to increased fetal adiposity levels (26, 40). Methodological considerations

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Strengths of this study were the prospective data collection from early pregnancy onwards and the large sample size. We had detailed childhood anthropometric measurements available. Follow-up data were available for only a subgroup of our study population. Mothers with offspring follow-up data available were more likely to be higher educated and to have a higher socio-economic status. This selection towards a more affluent population may affect the generalizability of our results. We measured maternal CRP-levels in blood samples that were processed within 24 hours after collection. Since the estimated half-life of CRP is approximately 19 hours, this may have caused some potential degradation of maternal CRP, which may have led to an underestimation of the observed associations. Maternal CRP-level was measured only once during pregnancy. Using repeated maternal CRP measurements throughout pregnancy is of interest as this could account for withinperson variability and allows for assessment of change of maternal CRP-levels during pregnancy in relation to offspring outcomes. CRP is a non-specific marker of maternal lowgrade systemic inflammation. To obtain further insight in the observed associations, it is of

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interest to assess the associations of more detailed maternal inflammatory markers, such as TNF-à, with offspring outcomes. We had detailed information about a large number of maternal socio-demographic and lifestyle-related confounding factors available in this study. However, because of the observational design, residual confounding due to unmeasured characteristics might still be an issue. In addition, information on some covariates was selfreported which may have resulted in underreporting of adverse lifestyle related characteristics. Conclusion

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Higher second trimester maternal plasma level of CRP, a non-specific marker of inflammation which is produced by the liver, was associated with higher childhood overall and central adiposity. Our findings are mainly of interest from an etiological perspective, as the effect size of the observed associations was relatively small. Further studies are needed to explore whether an increased obesity-mediated inflammatory state during pregnancy forms part of the causal mechanism that underlies the associations of maternal obesity during pregnancy with adverse cardio-metabolic outcomes in the offspring.

Acknowledgments SOURCES OF FUNDING This research was supported by grants from the National Institutes of Health (R37HD034568, K24 HD069408, R01 HL 64925, R01HL 75504, and P30 DK092924). RG received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement No 289346. We thank the staff and participants of Project Viva.

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References

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1. Drake AJ, Reynolds RM. Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction. 2010; 140:387–398. [PubMed: 20562299] 2. Denison FC, Roberts KA, Barr SM, Norman JE. Obesity, pregnancy, inflammation, and vascular function. Reproduction. 2010; 140:373–385. [PubMed: 20215337] 3. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. Jama. 1999; 282:2131–2135. [PubMed: 10591334] 4. Davi G, Guagnano MT, Ciabattoni G, Basili S, Falco A, Marinopiccoli M, et al. Platelet activation in obese women: role of inflammation and oxidant stress. Jama. 2002; 288:2008–2014. [PubMed: 12387653] 5. Ramsay JE, Ferrell WR, Crawford L, Wallace AM, Greer IA, Sattar N. Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. The Journal of clinical endocrinology and metabolism. 2002; 87:4231–4237. [PubMed: 12213876] 6. Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia. Seminars in immunopathology. 2007; 29:151–162. [PubMed: 17621700] 7. Challier JC, Basu S, Bintein T, Minium J, Hotmire K, Catalano PM, et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta. 2008; 29:274–281. [PubMed: 18262644] 8. Radaelli T, Varastehpour A, Catalano P, Hauguel-de Mouzon S. Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes. 2003; 52:2951–2958. [PubMed: 14633856]

Obesity (Silver Spring). Author manuscript; available in PMC 2017 June 01.

Gaillard et al.

Page 10

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

9. Stewart FM, Freeman DJ, Ramsay JE, Greer IA, Caslake M, Ferrell WR. Longitudinal assessment of maternal endothelial function and markers of inflammation and placental function throughout pregnancy in lean and obese mothers. The Journal of clinical endocrinology and metabolism. 2007; 92:969–975. [PubMed: 17192290] 10. Sen S, Simmons RA. Maternal antioxidant supplementation prevents adiposity in the offspring of Western diet-fed rats. Diabetes. 2010; 59(12):3058–65. [PubMed: 20823102] 11. Dahlgren J, Nilsson C, Jennische E, Ho HP, Eriksson E, Niklasson A, et al. Prenatal cytokine exposure results in obesity and gender-specific programming. American journal of physiology Endocrinology and metabolism. 2001; 281:E326–334. [PubMed: 11440909] 12. Radaelli T, Uvena-Celebrezze J, Minium J, Huston-Presley L, Catalano P, Hauguel-de Mouzon S. Maternal interleukin-6: marker of fetal growth and adiposity. Journal of the Society for Gynecologic Investigation. 2006; 13:53–57. [PubMed: 16378913] 13. Danielsen I, Granstrom C, Rytter D, Halldorsson TI, Bech BH, Henriksen TB, et al. Subclinical inflammation during third trimester of pregnancy was not associated with markers of the metabolic syndrome in young adult offspring. Obesity (Silver Spring). 2014; 22:1351–8. [PubMed: 24167021] 14. Yeh ET. CRP as a mediator of disease. Circulation. 2004; 109:II11–14. [PubMed: 15173057] 15. Gillman MW, Rich-Edwards JW, Rifas-Shiman SL, Lieberman ES, Kleinman KP, Lipshultz SE. Maternal age and other predictors of newborn blood pressure. J Pediatr. 2004; 144:240–245. [PubMed: 14760269] 16. Oken E, Baccarelli AA, Gold DR, Kleinman KP, Litonjua AA, De Meo D, et al. Cohort Profile: Project Viva. International journal of epidemiology. 2015; 44:37–48. [PubMed: 24639442] 17. World Medical Association I. Declaration of Helsinki. Ethical principles for medical research involving human subjects. Journal of the Indian Medical Association. 2009; 107:403–405. [PubMed: 19886379] 18. Rich-Edwards JW, Mohllajee AP, Kleinman K, Hacker MR, Majzoub J, Wright RJ, et al. Elevated midpregnancy corticotropin-releasing hormone is associated with prenatal, but not postpartum, maternal depression. J Clin Endocrinol Metab. 2008; 93:1946–1951. [PubMed: 18303075] 19. Pitiphat W, Gillman MW, Joshipura KJ, Williams PL, Douglass CW, Rich-Edwards JW. Plasma Creactive protein in early pregnancy and preterm delivery. American journal of epidemiology. 2005; 162:1108–1113. [PubMed: 16236995] 20. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital and health statistics Series 11, Data from the national health survey. 2002:1–190. 21. Boeke CE, Oken E, Kleinman KP, Rifas-Shiman SL, Taveras EM, Gillman MW. Correlations among adiposity measures in school-aged children. BMC pediatrics. 2013; 13:99. [PubMed: 23799991] 22. Wells JC. A critique of the expression of paediatric body composition data. Arch Dis Child. 2001; 85(1):67–72. [PubMed: 11420208] 23. Oken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC pediatrics. 2003; 3:6. [PubMed: 12848901] 24. Oken E, Ning Y, Rifas-Shiman SL, Rich-Edwards JW, Olsen SF, Gillman MW. Diet during pregnancy and risk of preeclampsia or gestational hypertension. Annals of epidemiology. 2007; 17:663–668. [PubMed: 17521921] 25. Regnault N, Gillman MW, Rifas-Shiman SL, Eggleston E, Oken E. Sex-specific associations of gestational glucose tolerance with childhood body composition. Diabetes care. 2013; 36:3045– 3053. [PubMed: 23877978] 26. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. European cytokine network. 2006; 17:4–12. [PubMed: 16613757] 27. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105:1135– 1143. [PubMed: 11877368]

Obesity (Silver Spring). Author manuscript; available in PMC 2017 June 01.

Gaillard et al.

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Author Manuscript Author Manuscript Author Manuscript

28. Calle MC, Fernandez ML. Inflammation and type 2 diabetes. Diabetes & metabolism. 2012; 38:183–191. [PubMed: 22252015] 29. Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR, et al. Emerging Risk Factors C. C-reactive protein, fibrinogen, and cardiovascular disease prediction. The New England journal of medicine. 2012; 367:1310–1320. [PubMed: 23034020] 30. Timpson NJ, Nordestgaard BG, Harbord RM, Zacho J, Frayling TM, Tybjaerg-Hansen A, et al. Creactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. Int J Obes (Lond). 2011; 35:300–308. [PubMed: 20714329] 31. Madan JC, Davis JM, Craig WY, Collins M, Allan W, Quinn R, et al. Maternal obesity and markers of inflammation in pregnancy. Cytokine. 2009; 47:61–64. [PubMed: 19505831] 32. Friis CM, Paasche Roland MC, Godang K, Ueland T, Tanbo T, Bollerslev J, et al. Adiposity-related inflammation: effects of pregnancy. Obesity (Silver Spring). 2013; 21:E124–130. [PubMed: 23505192] 33. Ernst GD, de Jonge LL, Hofman A, Lindemans J, Russcher H, Steegers EA, et al. C-reactive protein levels in early pregnancy, fetal growth patterns, and the risk for neonatal complications: the Generation R Study. American journal of obstetrics and gynecology. 2011; 205:132 e131–112. [PubMed: 21575931] 34. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. The New England journal of medicine. 2008; 359:61–73. [PubMed: 18596274] 35. Farah N, Hogan AE, O'Connor N, Kennelly MM, O'Shea D, Turner MJ. Correlation between maternal inflammatory markers and fetomaternal adiposity. Cytokine. 2012; 60:96–99. [PubMed: 22726456] 36. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009; 114:1326–1331. [PubMed: 19935037] 37. Roberts KA, Riley SC, Reynolds RM, Barr S, Evans M, Statham A, et al. Placental structure and inflammation in pregnancies associated with obesity. Placenta. 2011; 32:247–254. [PubMed: 21232790] 38. Saben J, Lindsey F, Zhong Y, Thakali K, Badger TM, Andres A, et al. Maternal obesity is associated with a lipotoxic placental environment. Placenta. 2014; 35:171–177. [PubMed: 24484739] 39. Zhu MJ, Du M, Nathanielsz PW, Ford SP. Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the mid-gestation sheep placenta. Placenta. 2010; 31:387–391. [PubMed: 20185176] 40. Retnakaran R, Hanley AJ, Raif N, Connelly PW, Sermer M, Zinman B. C-reactive protein and gestational diabetes: the central role of maternal obesity. J Clin Endocrinol Metab. 2003; 88:3507– 3512. [PubMed: 12915627]

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What is already known about this subject? •

Maternal prepregnancy obesity is an important risk factor for obesity in the offspring



An increased maternal obesity mediated pro-inflammatory state during pregnancy may be part of the mechanism underlying this association



Maternal obesity is associated with a higher maternal CRP-level during pregnancy, a non-specific circulating marker of systemic inflammation produced by the liver

What does your study add?

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Maternal second trimester plasma level of CRP is associated with higher mid-childhood total body fat mass and abdominal fat mass in the offspring



These associations were not explained by maternal body mass index, gestational diabetes, gestational hypertensive disorders or birth characteristics

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TABLE 1

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Characteristics of mothers and their children in Project Viva (N=1116) Characteristic

Total group

CRP1.2 mg/L

Age, mean (SD), years

32.4 (5.0)

32.4 (5.0)

32.4 (5.0)

Gestational age at intake, mean (SD), wks

10.4 (2.5)

10.5 (2.5)

10.4 (2.4)

Height, mean (SD), m

1.7 (0.1)

1.7 (0.1)

1.7 (0.1)

Prepregnancy weight, mean (SD), kg

67.4 (15.3)

63.6 (12.2)

71.1 (17.1)

Prepregnancy Body Mass Index, mean (SD), kg/m2

24.6 (5.2)

23.3 (4.0)

26.0 (5.9)

Education, at least college graduate, N (%)

788 (70.6%)

413 (74.7%)

375 (66.6%)

Ethnicity, White, N (%)

819 (73.4%)

415 (75.1%)

404 (71.8%)

Parity, Nulliparous, N (%)

531 (47.6%)

266 (48.2%)

265 (47.0%)

Never

770 (69.0%)

385 (69.6%)

385 (68.3%)

Former

228 (20.4%)

119 (21.5%)

109 (19.4%)

Continued

118 (10.6%)

49 (8.9%)

69 (12.3%)

2126 (602)

2117 (576)

2135 (626)

28.0 (27.1–28.6)

28.0 (27.1–28.6)

28.0 (27.1–28.6)

1.2 (0.6–2.1)

0.6 (0.3–0.8)

2.1 (1.6–2.9)

994 (89.0%)

508 (91.9%)

486 (86.2%)

Maternal characteristics

Smoking during pregnancy, N (%)

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Total energy intake during pregnancy, kcal/day, Maternal inflammatory biomarkers Gestational age at measurement, median (IQR), wks CRP, median (IQR range), mg/L Maternal pregnancy complications Gestational hypertensive disorder, N (%) Normal

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Chronic hypertension

15 (1.4%)

4 (0.8%)

11 (2.0%)

Gestational hypertension

71 (6.4%)

26 (4.7%)

45 (8.0%)

Preeclampsia

36 (3.2%)

14 (2.6%)

22 (3.8%)

Normal

932 (83.5%)

471 (85.3%)

461 (81.8%)

Failed GCT normal OGTT

101 (9.1%)

54 (9.9%)

47 (8.4%)

Impaired glucose tolerance

32 (2.9%)

11 (1.9%)

21 (3.7%)

Gestational diabetes

50 (4.5%)

16 (2.9%)

34 (6.1%)

538 (48.2%)

264 (47.8%)

274 (48.6%)

Gestational diabetes, No (%)

Birth characteristics Females, N. (%) Gestational age at birth, median (IQR range), weeks

39.7 (38.9–40.6)

39.7 (38.9–40.6)

39.7 (38.7–40.6)

Birth weight, mean (SD), g

3507 (537)

3483 (512)

3530 (559)

Birth weight for gestational age, mean (SD), z-score

0.22 (0.96)

0.17 (0.93)

0.27 (0.98)

3.2 (3.1–3.3)

3.1 (3.1–3.3)

3.2 (3.1–3.3)

16.5 (1.5)

16.3 (1.3)

16.7 (1.6)

Body mass index, mean (SD), z-score

0.43 (1.04)

0.30 (0.97)

0.57 (1.08)

Waist circumference, mean (SD), cm

51.3 (3.5)

51.0 (3.1)

51.6 (3.9)

Early childhood characteristics

Author Manuscript

Age at follow up, median (IQR range), yr Body mass index, mean (SD),

kg/m2

Mid-childhood characteristics

Obesity (Silver Spring). Author manuscript; available in PMC 2017 June 01.

Gaillard et al.

Page 14

Characteristic

Total group

CRP1.2 mg/L

Age at follow up, median (IQR range), yr

Author Manuscript

7.7 (7.3–8.3)

7.7 (7.3–8.2)

7.7 (7.3–8.3)

Total fat mass index, mean (SD), kg/m2

4.3 (1.8)

4.0 (1.5)

4.6 (2.0)

Fat free mass index, mean (SD), kg/m2

13.0 (1.4)

12.8 (1.3)

13.1 (1.4)

kg/m2

1.4 (0.8)

1.3 (0.7)

1.5 (0.9)

17.1 (2.9)

16.6 (2.4)

17.5 (3.2)

Body mass index, mean (SD), z-score

0.35 (0.98)

0.20 (0.94)

0.49 (0.99)

Waist circumference, mean (SD), cm

59.6 (7.7)

58.6 (6.8)

60.5 (8.3)

Truncal fat mass index, mean (SD), Body mass index, mean (SD),

kg/m2

1

Values represent means (SD), median (IQR range) or number of subjects (%).

Author Manuscript Author Manuscript Author Manuscript Obesity (Silver Spring). Author manuscript; available in PMC 2017 June 01.

Gaillard et al.

Page 15

TABLE 2

Author Manuscript

Bivariate associations of maternal characteristics and pregnancy outcomes with maternal CRP level in the second trimester of pregnancy (N=1116) Maternal characteristics

Difference in CRP Levels (mg/L) (95%CI)

Maternal age

Maternal inflammation during pregnancy and childhood adiposity.

Maternal pre-pregnancy obesity is associated with offspring obesity. Underlying mechanisms may involve a maternal obesity-mediated proinflammatory sta...
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