Clinical Study Maternal BMI IGF I Levels and Birth

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Clinical Study Maternal BMI Division of Maternal Fetal Medicine Department Obstetrics and Gynecology Carolina Cord Blood Bank


2 International Journal of Pediatrics, 1 Introduction 2 2 Data Collection Interviewer or self administered ques. tionnaires were obtained at the time of enrollment and. Low birth weight LBW and high birth weight HBW are medical records during pregnancy were abstracted at partu. both important indicators of suboptimal intrauterine devel rition Data collected using questionnaires included socio. opment and have been linked to risk of several chronic dis demographic characteristics reproductive factors and life. eases later in life HBW has been associated with childhood style factors such as cigarette smoking and self reported. and adult obesity 1 and some cancers including breast 2 pregnancy anthropometric measurements Information on. and prostate cancer 3 whereas LBW is a consistently iden anthropometric measurements during pregnancy birth out. tified risk factor for cardiovascular disease CVD 4 5 and comes including birth weight and length was abstracted. type 2 diabetes T2D 6 7 from medical records Umbilical cord blood specimens were. IGF I is a mitogenic and antiapoptotic paracrine growth also collected at birth as previously described 36 37. factor expressed in all fetal organs 8 9 and is essential in. fetal and neonatal growth differentiation and development 2 3 IGF I Cord Blood Levels Plasma concentrations of IGF I. 10 14 Several lines of evidence suggest that IGF I levels were measured using microplate enzyme linked immunosor. are associated with birth weight 15 26 furthermore higher bent assays ELISA Diagnostic Systems Laboratories Web. IGF I levels are associated with higher BW but not with lower ster TX USA according to the manufacture instructions. birth weight 16 17 26 In adulthood elevated concentra and triplicate assays per sample were performed Absorbance. tions of IGF I are associated with an increased risk of obesity was read using a microplate reader DSL Webster TX USA. and many cancers including breast lung head and neck col The plasma IGF I concentrations ranged from 3 65 ng L to. orectal pancreas synovial sarcoma and prostate cancer 26 418 36 ng L and assay sensitivity was 2 2 ng mL. 31 Although concentrations of circulating IGF I levels vary. considerably by race ethnicity and maternal prepregnancy 2 4 Statistical Analysis Infant birth weight was normally. obesity few studies included African American women 24 distributed and was used as a continuous variable Because. 26 an ethnic group that has an almost 9 higher BMI both high birth weight HBW and low birth weight LBW. than European American women 32 Furthermore studies have been linked to maternal obesity 1 we also analyzed. examining both maternal obesity an increasingly common birth weight as a categorical variable LBW 2500 g normal. condition and race ethnicity are few 33 35 Herein we birth weight 2500 4000 g and HBW 4000 g We used chi. examine associations between IGF I levels in relation to body squared tests to examined distribution of factors that have. size at birth in a cohort of infants born to obese and non been previously associated with birth weight 4000 g and. obese African American and White women 2500 g in relation to maternal age categorized as 18 25 26. 30 and 30 years prepregnancy mothers body mass index. BMI categorized as 30 and 30 kg m2 race ethnicity, 2 Subjects and Methods categorized as White African American and other and. maternal education categorized as less than college college. Ethics Statement The study protocol was approved by the and graduate level education maternal smoking and infant. Duke University Institutional Review Board IRB We gender Although some of these factors were not statistically. obtained written informed consent from all participants significantly associated with BW in this study we adjusted for. involved in our study We also obtained informed written maternal age BMI race education delivery route gestational. consent from carers or guardians on the behalf of the age at delivery maternal smoking during pregnancy and. minors children participants involved in our study infant gender as they are associated with BW and IGF I in. the population The distribution of IGF I levels departed from. normality and thus they were categorized into tertiles We. 2 1 Study Participants Pregnant women were enrolled as then dichotomized at the top tertile 67th percentile and. part of the Newborn Epigenetics STudy NEST a prospective compared this tertile high IGF I 67th percentile to the. study of women and their infants Detailed methods for remainder low IGF I 67th percentile Linear regression. enrollment of study participants have been reported else models were used to examine the extent to which IGF I levels. where 36 Briefly pregnant women who were 18 years and differed by birth weight as described in 36 All statistical. older and who planned to give birth at Duke University or analyses were conducted in SAS v9 2 SAS Institute Inc Cary. Durham Regional Hospitals were recruited from Durham NC USA. County NC prenatal clinics HIV 1 infected women were. excluded Of the 1101 women approached 940 85 con 3 Results. sented and were enrolled most of the enrolled sample 81. was successfully followed to delivery 757 IGF I Approximately 4 of the 251 newborns were born 2500 g. analyses were performed on the first 251 women and had a and 8 were born 4000 g Mean gestational age at delivery. gestational age 37 weeks Data from these participants were was 39 weeks SD 1 14 Table 1 summarizes the charac. comparable to participants in whom IGF I was not measured teristics of the study participants in relation to birth weight. with respect to maternal age gestational age race ethnicity Most low birth weight infants 2500 g were born to African. and maternal prepregnancy BMI Americans 89 cigarette smokers before and during. International Journal of Pediatrics 3,Table 1 Characteristics of study participants. Birth weight,Characteristic,2500 g 10 2500 4000 g 218 4000 21 value. Maternal age at enrollment yrs 0 79,18 25 78 4 40 67 31 6 28 5.
26 30 76 4 40 65 30 6 28 5,30 97 2 20 86 39 9 43,Maternal BMI before pregnancy 0 17. 30 159 7 87 5 140 71 11 55,30 66 1 12 5 56 29 9 45. Mean BMI 26 61 SD 4 8 28 4 SD 9 4 31 3 SD 12 3 0 37. Race ethnicity 0 1,African American 126 8 89 110 51 8 38. White 97 1 11 85 39 9 43,Other 25 0 0 21 9 7 4 19,Education 0 18. High School HS Graduate GED 95 6 67 79 39 9 43,Some College College Graduate.
3 33 136 63 12 57,Graduate education 152,Maternal smoking 0 14. Never smoked 135 2 20 120 55 13 62,Smoked during pregnancy 42 3 30 36 17 1 5. Quit smoking before pregnancy 74 5 50 62 28 7 33,Gender of infant 0 12. Male 105 5 50 86 39 13 62,Female 146 5 50 132 61 8 38. Delivery route 0 75,Vaginal 149 7 70 131 61 10 48,Caesarean section 101 3 30 86 39 11 52.
Gestational age at delivery in weeks 0 006,Mean SD 37 0 22 39 1 11 39 0 93. IGF I 0 12,3rd Tertile 170 5 50 153 70 11 52,3rd Tertile 81 5 50 65 30 10 48. Numbers do not necessarily add up due to missing values. pregnancy 80 and those with a lower educational achieve significant Infants with higher IGF I levels were comparable. ment 67 however the differences were not statistically to those with lower levels with respect to maternal age. significant LBW were however comparable to infants born 0 65 race 0 83 maternal education 0 38 mater. 2500 4000 g with respect to maternal age HBW infants nal smoking 0 63 obesity 0 28 and gestational. were comparable to those born 2500 4000 g with respect to age 0 91 Table 2 although they may differ by delivery. education and maternal smoking although they were more route 0 14. frequently born to white women and those with a BMI 30 Table 3 shows coefficient estimates s and their stan. before pregnancy No statistically significant differences in dard errors SEs for five multivariate linear regression. IGF I levels were found between birth weight 2500 g infants models of birth weight on IGF I levels in which IGF I 67th. and birth weight 4000 g infants however birth weight percentile concentrations or 3rd tertile served as referents. 2500 g infants were born two weeks earlier than infants born one for all participants one restricted to African Americans. 2500 4000 g and birth weight 4000 g infants 0 006 one restricted to Whites one restricted to maternal BMI 30. Table 1 and one restricted to maternal BMI 30 The first model. Median IGF I concentration in newborns was 35 55 ng L shows that after adjusting for infant gender race gestational. IQR 17 35 65 68 with a mean of 58 92 ng L Birth weight age at delivery delivery route maternal BMI and smoking. ranged between 2000 and 5160 g mean 3315 g SD 486 during pregnancy infants in the upper tertile of IGF I were. Infants with higher levels of IGF I 3rd tertile were born larger at birth 230 46 se 58 0 0 0001 corre. slightly heavier than infants with lower IGF I concentrations sponding to 130 g increased birth weight in infants born to. 3rd tertile although the differences were not statistically those with high IGF I levels Table 3 We also found that this. 4 International Journal of Pediatrics, Table 2 Characteristics of study participants by Infant IGF I levels ng L. IGF I Levels,3rd tertile 170 3rd tertile 81,Maternal age at enrollment yrs 0 65. 18 25 78 50 29 28 35,26 30 76 54 32 22 27,30 97 66 68 31 38.
Maternal BMI 0 28,30 159 104 68 55 75,30 66 48 32 18 25. African American 126 86 51 40 500,White 9 64 38 33 4111. Other 25 18 11 7 9,Education 0 38,High School HS Graduate GED 95 67 40 28 35. Some College College Graduate,99 60 53 65,Graduate Education 152. Delivery route 0 14,Vaginal 149 94 55 55 68,Caesarean section 101 75 44 26 32.
Maternal smoking 0 63,Never smoked 135 95 56 40 49. Smoked during periconception 42 27 16 15 19,Quit smoking before periconception 74 48 28 26 32. Gender of infant 0 29,Male 105 75 44 30 37,Female 146 95 56 51 63. Mean Gestational age in weeks SD 39 1 16 39 1 08 0 91. Mean Birth weight SD 3273 460 6 3414 74 523 5 0 56. Numbers do not necessarily add up due to missing values. Unadjusted, Table 3 1 Adjusted regression coefficients and standard errors SE for the associations between newborn IGF I and Birth Weight in 251. African American and White infants,Birth weight, All African American Whites Maternal BMI 30 Maternal BMI 30.
251 126 97 159 66, coefficient SE coefficient SE coefficient SE coefficient SE coefficient SE. value value value value value, High IGF I 230 46 58 0 0 0001 280 98 90 24 0 002 202 05 89 72 0 02 122 31 62 65 0 05 617 78 134 68 0 0001. Female infants 51 7 55 68 0 35 67 36 80 54 0 40 172 47 90 08 0 06 137 68 62 1 0 03 146 20 111 10 0 19. White Race 240 60 63 07 0 0002 202 11 46 26 0 0001 35 21 87 27 0 68. High maternal, 201 68 62 55 0 001 261 81 82 95 0 002 161 64 125 81 0 2. Gestational age at, 205 92 23 84 0 0001 206 58 35 92 0 0001 172 63 37 79 0 0001 213 25 24 9 0 0001 187 13 54 47 0 001. Smoking during, 8 11 31 02 0 79 5 90 47 40 0 90 39 63 47 26 0 40 46 36 33 28 0 16 2 36 68 16 0 97.
Delivery route 151 57 56 58 0 008 229 73 84 34 0 008 74 06 86 27 0 40 146 23 62 58 0 03 178 73 111 78 0 11. Factors mutually adjusted for each other IGF I levels infant gender race maternal BMI maternal smoking delivery route and gestational age at delivery. to predict birth weight, Referents are individuals with lower 3rd Tertile IGF I at delivery. Referents are male infants,Referents are African Americans. Referents are BMI 30,Referents are lower gestational age. Referents are nonsmoking mothers,Referents are vaginal delivery infants. International Journal of Pediatrics 5, association was slightly higher in African American infants European Maori South Asian and Pacific Islands cohorts.
0 002 compared to White infants 0 02 However 33 47 48 supporting the hypothesis that IGF I and insulin. the cross product term for race and IGF I was not significant resistance perhaps driven by genetic factors may play a. 0 5 Since the prevalence of BMI 30 in African role in fetal growth IGF I levels in pregnant women have. American women in our study is higher 67 compared to been positively correlated with maternal body weight 33. Whites 24 0 0001 we examined the role of mater 49 Maternal insulin sensitivity has been proposed as an. nal BMI on the relationship between IGF I levels and birth important endogenous environmental factor in fetal size 50. weight The pair of models restricted by BMI revealed that Maternal hyperglycemia a correlate of obesity even con. the association of IGF I levels and infant size was limited to sidered in the normal range may affect fetal weight 51. women with a BMI 30 617 78 se 134 68 Together these findings suggest that the IGF axis may play. 0 0001 We found a strong positive association in infants a key role in fetal overgrowth and maternal obesity may be. born to obese women the cross product term for maternal an important driver in placental IGF axis concentrations and. BMI and IGF I was 0 0004 thus increasing the risk for higher birth weight and infant. obesity in childhood, The main limitation of this study was relatively small sam. 4 Discussion ple size for analyses restricted to maternal BMI BMI 30. Our key finding was a positive association among term versus BMI 30 however findings are consistent with the. infants with elevated IGF I levels and an increased risk expected role of IGF I and IGF I values themselves range. of higher birth weight This positive association was most median and skewness of IGF I levels and the magnitude of. apparent in infants born to obese women High birth weight the positive associations with higher birth weight and growth. and high IGF I levels a potent mitogen have been linked are similar to previous reports 25 26 Also we relied on a. to CVD T2D and some cancers 2 7 Importantly our data single measure of IGF I levels at delivery however it was not. also demonstrate that after accounting for maternal obesity feasible to obtain IGF I levels before birth in these infants. before pregnancy the influence of ethnicity race on the However at least postnatally interindividual variation seems. association between IGF I and birth weight an important stable and most studies relating cord blood IGF I protein. risk factor for common chronic diseases is dramatically concentrations and birth weight reported single measure. diminished ments at birth 18 52 and findings are similar Consideration. The extent to which the positive association between should also be given to the fact that infant s race ethnicity. IGF I at birth and early postnatal growth that is maintained is the self reported mother s race ethnicity and the study. during life course to adulthood is still unclear although a few is predominantly African Americans and Whites Future. studies report that elevated IGF I levels measured at birth are studies should use ancestral markers to further clarify race. associated with age 4 5 year obesity 38 39 specific associations Another limitation was that we did. IGF I levels found in this study median 36 ng L ICR not measure other components of the IGF axis including. 17 ng L 66 ng L are slightly lower than those reported in growth hormone insulin IGF binding proteins IGFBP1 5. previous studies 25 however our findings that higher IGF I and receptors IGF 1R and 2R concentrations in the new. levels at birth are associated with increased birth weight are borns to further establish the potential implication of other. consistent with those of others 18 and with reports which components of the IGF system in fetal growth However the. found positive associations between both placental 40 and assay used measured total cord blood IGF I in circulation. cord plasma IGF I concentrations and lower birth weight Despite these limitations our findings support the hypothesis. infants compared with IGF I concentrations in normal birth that elevated IGF I is an important growth factor in early. weight infants 19 41 44 Our findings however contrast development that has been linked to a number of common. with those of Wang et al 45 and Deiber et al 46 who chronic diseases regardless of race ethnicity. found low birth weight associated with higher IGF I in In summary we found that elevated IGF I levels in. populations of infants born to White women Divergent newborns increase the risk of higher birth weight in African. findings may be due in part to lower incidence of maternal American and White infants Our findings also suggest that. obesity among European women the strongest association. maternal BMI 30 may modify positive associations between. between IGF I and birth weight was found in infants born. IGF I and higher birth weight supporting the idea that. to obese women It is speculated that such differences may. involve the IGF axis through IGF I and growth hormone maternal obesity may be key in increasing the risk of higher. GH signaling which differ by obesity 21 23 47 birth weight in the newborns an important risk factor for. These race ethnic similarities exist despite IGF I concen several chronic diseases including cancer These findings. trations being generally lower in African American than in suggest that the potential utility of IGF I levels as a marker of. White neonates born with normal weight as shown in male future obesity in the offspring is limited to those born to obese. 25 and in female newborns 26 and in studies performed women As the prevalence of maternal obesity continues to. in adults 33 increase larger multiethnic studies with followup at shorter. Our findings that elevated IGF I levels are associated with intervals that allow for maternal obesity specific analyses. increased birth weight in infants born to obese mothers are required to further elucidate the nature of the positive. are consistent with at least three other studies comprising association between IGF I levels and higher birth weight. 6 International Journal of Pediatrics, Conflict of Interests 14 M N Pollak E S Schernhammer and S E Hankinson Insu. lin like growth factors and neoplasia Nature Reviews Cancer. The authors declare no conflict of interests vol 4 no 7 pp 505 518 2004. 15 K Langford W Blum K Nicolaides J Jones A McGregor. Acknowledgments and J Miell The pathophysiology of the insulin like growth. factor axis in fetal growth failure a basis for programming by. 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IGF I levels in childhood are related to both current body height and birthweight Pediatrics International vol 42 no 1. composition and early postnatal growth rate Journal of Clinical pp 31 36 2000. Endocrinology and Metabolism vol 87 no 3 pp 1041 1044. 39 C H D Fall A N Pandit C M Law et al Size at birth and. plasma insulin like growth factor 1 concentrations Archives of. Disease in Childhood vol 73 no 4 pp 287 293 1995, 40 S K Akram C Carlsson Skwirut Z A Bhutta and O Soder. Placental IGF I IGFBP 1 zinc and iron and maternal and. MEDIATORS of,INFLAMMATION,The Scientific Gastroenterology Journal of. World Journal,Hindawi Publishing Corporation,Research and Practice.
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