Maternal and Paternal and Sex- Specific Offspring Linear Growth From Second Trimester to Mid-Childhood

The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters

Citation Gross, Emily Ann. 2017. Maternal and Paternal Height and Sex- Specific Offspring Linear Growth From Second Trimester to Mid- Childhood. Doctoral dissertation, Harvard Medical School.

Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:40620326

Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Scholarly Report submitted in partial fulfillment of the MD Degree at Harvard Medical School

1 February 2017

Emily Ann Gross, B.S.

Maternal and paternal height and sex-specific offspring linear growth from second trimester to mid-childhood

Dr. Matthew Gillman, MD, SM, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Care Institute

TITLE: Maternal and paternal height and sex-specific offspring linear growth from second trimester to mid-childhood Emily Gross, Sheryl L. Rifas-Shiman, Karen Switkowski, Line Klingen Haugaard, Matthew W. Gillman Background: Offspring height and linear growth rate is known to be associated with parental height; the strength of this association may not be constant. Aim: To study the associations of parental height with sex-specific offspring length/height changes in utero through mid-childhood. Methods: We analyzed data from 1395 participants in Project Viva, a prospective cohort study of pregnant women and their children. Multivariable linear regression models were used to examine associations of maternal and paternal height with offspring length/height change during growth periods beginning during the 2nd trimester and extending into mid-childhood (median age 7.7). Offspring sex-specific analysis was performed. Results: Among female and male offspring combined, for every z-score increment in maternal height, offspring length z-score from 2nd trimester to birth increased by 0.14 (95% C.I. 0.09, 0.20). For paternal height the increase was 0.11 (0.05, 0.16). In this same age period, models stratified by sex showed a stronger maternal than paternal association for female offspring (maternal 0.21 [0.11, 0.31], paternal 0.08 [-0.01, 0.17]), but not for males (maternal 0.10 [0.03, 0.18], paternal 0.14 [0.06, 0.22]). Parental height was a weaker predictor of later linear growth; for height change from early to mid-childhood, maternal and paternal height effect estimates were 0.07 (0.04, 0.10) and 0.06 (0.03, 0.09), respectively. Conclusions: Parental height effects on linear growth rates are greatest during early stages of development. Among female offspring, maternal height was more strongly associated with prenatal linear growth than was paternal height.

Table of contents

Glossary of Abbreviations Section 1: Introduction Section 2: Student role Section 3: Methods Section 4: Results Section 5: Discussion, Limitations, Conclusions Section 6: Acknowledgements References Tables and Figures

Glossary of Abbreviations

BMI: CI: GA: GH: ICP: Infancy-childhood- LMP: Last menstrual period

Introduction A child with tall parents is likely to be taller than his or her peers who have shorter parents. Although estimates of height are as high as 80% [1,2] and genome-wide association studies have identified 180 loci associated with height [3], these common variants explain only ~16% of variation in adult height [4], suggesting height heritability is only partially genetic. Understanding determinants of height is important, as height can be a marker of disease risk. In the developed world, shorter adults are at an increased risk of coronary artery disease [5] and mortality due to cardiovascular and respiratory disease [6-8]. Alternatively, taller adults are at increased risk for developing cancer, including colorectal, prostate, breast, and endometrial [9], and taller children have higher systolic blood pressure [10]. Various studies have reported associations of maternal, paternal, and mid-parental height with static length/height measures during prenatal and early childhood periods through age 3 years. In one study that combined pre- and post-natal linear growth, among 3370 participants in the Generation R Study, Mook-Kanamori et al. found that mother’s height was more strongly associated with offspring length from in utero through 3 years of age than was father’s height [11]. Similarly, the EDEN mother-child cohort of 1752 participants showed an association of maternal but not paternal height with femur length in the 3rd trimester [12]. However, in a study of 567 British children, Knight et al. showed that paternal height was independently associated with birth length to the same degree as maternal height [13]. These studies did not stratify analyses by offspring sex, and they assessed femur length and offspring length as static measures. Examining height at a moment in time instead of linear growth change fails to capture the dynamicity of height development. Change in length/height is a predictor of childhood and adult health outcomes. For example, within the same cohort as in this study, change in linear growth from 3 to 7 years of age was associated with an increase in systolic blood pressure [10]. Additionally, in a study of 565 Indian children, greater length gain in utero and in infancy was associated with increased adult bone mineral content [14]. In an attempt to understand determinants of offspring linear growth, one study examined the association between parental height and change in femur length in the prenatal period. In that study of 577 parent-offspring pairs in India, neither maternal nor paternal height was associated with growth from 17 to 29 weeks, while maternal height trended towards a stronger association with femur length change from 29 weeks until birth than paternal height [15]. However, that study did not stratify results by offspring sex and the analysis did not carry forward into childhood. The purpose of our analysis was to examine the relative contributions of maternal and paternal height to offspring height/length change depending on offspring sex and stage of development, beginning in utero and extending through mid-childhood. We hypothesized that offspring length change would have a stronger association with maternal height than paternal height because changes in maternal height may directly influence the physical growing space of the . We further hypothesized that female lengths/ would be more strongly associated with maternal height and male lengths with paternal height, and that the association of either parental height with child linear growth would be weaker in later growth periods.

Student Role My role involved analysis of existing anthropometric data collected in Project Viva. My project built on previous work done in this cohort that looked at the association of maternal pre- BMI and fetal biometric measures of abdominal circumference, femur length, and bi-parietal diameter. Under the guidance of my mentor Dr. Matthew Gillman, I worked on study design and analysis of fetal biometric measures (femur length), and expanded to also examine childhood metrics (linear growth). My data analysis consisted of performing linear regressions adjusted for covariates using SAS software, with the assistance of Project Viva statistician Sheryl Rifas-Shiman. I have drafted a manuscript detailing our work and will submit it for publication.

Methods Participants We studied mother/father/offspring triads in Project Viva, a prospective, observational, cohort study of pregnant women and their children. During the years 1999-2002, Project Viva staff recruited pregnant women at their initial prenatal visit at eight offices of Atrius Harvard Vanguard Medical Associates, a large multispecialty urban/suburban group practice in eastern Massachusetts. Details of recruitment and retention procedures are available elsewhere [16]. All mothers enrolled in the Project Viva cohort study provided informed consent. The subjects committee of Harvard Pilgrim and Brigham and Women’s hospital granted approval for all study protocols, and all procedures were carried out in a manner consistent with established ethical standards. Of the 2128 mothers who delivered a live singleton , we excluded 69 who lacked either maternal or paternal height measures. Of the remaining 2059 offspring, we excluded 664 because they did not have at least two consecutive length/height measurements (e.g. femur and birth length, early-childhood and mid-childhood heights), which were necessary to estimate length/height change. Thus, our sample for analysis included 1395 participants. Of note, not all 1395 participants are represented in each growth interval, as many are missing one or more length/height measurement. Measures The two parental exposures of interest in this study were maternal and paternal height. Both measures were self-reported by the mother at her first study visit in early pregnancy. Though we have not validated the use of self-reported maternal and paternal heights for our particular cohort, other studies have demonstrated a high correlation between self-reported and measured heights in adults [17-18]. Maternally reported paternal height may be less accurate. Among 241 families in a pediatric endocrinology clinic, Braziuniene et al. reported that mothers overestimated their partner’s height by a mean of 3.7 cm, while the same mothers over-reported their own heights by only 0.5 cm. However, the correlation coefficient between mother-reported and measured paternal height was not included in the study; overestimation by mothers would have little effect on results if reported and measured values were highly correlated. Primary outcomes of interest were measures of linear growth from the prenatal period through mid-childhood. From routine early 2nd trimester ultrasound (16-20 weeks) we obtained measures of femur length, and we calculated gestational age at the date of ultrasound based on the mother’s LMP (last menstrual period). Similar to our previous analyses [20], we avoided using ultrasound data for both dating and growth by excluding femur length measurements from women who did not have a normal and certain LMP, and whose gestational age indicated by the ultrasound was ≥ 10 days different than the predicted gestational age based on LMP. One Project Viva research assistant measured birth length with the help of an available parent, nurse, or other research assistant using the recumbent length-board method and measuring to the nearest 0.1 cm; the recumbent length-board method was also used at the infancy visit (5.2-9.9 months, median 6.3 months). At the early childhood (2.8-6.2 years, median 3.2 years) and mid-childhood (6.6- 10.9 years, median 7.7 years) visits, trained research assistants measured child height with a calibrated stadiometer (Shorr Productions, Olney, MD). We converted all length/height measures into age- and sex specific z-scores. We used internal sex-specific z-scores for femur length, adjusted for gestational age, due to lack of a reference data set. We calculated age- and sex-specific length/height z-scores for birth and 6 month length, and early and mid-childhood height using the CDC’s 2000 reference data based on exact age at time of measurement [21]. We then created height change variables by subtracting length or height z-score at one time interval from the z-score at the following time interval. Thus our primary outcomes were differences in length/height z-scores as follows: 2nd trimester femur length to birth length, birth length to infancy length (6.3 months), infancy length to early childhood height (median 3.2 years), and early to mid-childhood height (median 7.7 years). Mothers reported information about their age, education, marital status, parity, race/ethnicity and smoking status; child sex and race/ethnicity; and household income via structured interviews and questionnaires. We extracted birth weight from the hospital medical record. We calculated pre-pregnancy BMI (kg/m2) from maternal self-reported height and pre- pregnancy weight. Data analysis We first investigated bivariate relationships between the main exposures of parental heights as continuous z-scores, outcomes of change in length/height z-scores for offspring as continuous z-scores, and other covariates. Our main analytic approach was multivariable linear regression to assess the associations of maternal and paternal height z-scores with length/height z-score changes in offspring. Model 0 included the main exposures and child sex. Model 1 additionally included the length/height z-score measured at the start of the given age interval, to adjust for potential slower growth that might occur following a period of accelerated growth, or faster growth after a period of retarded growth. Model 2 added other factors with the potential to alter child growth, namely maternal pre-pregnancy BMI, smoking during pregnancy, household income, and child race/ethnicity and gestational age at birth. Adjusting for paternal BMI and offspring age at the end of a growth interval did not change the results. In addition, we stratified the analyses by male and female offspring, and performed stratum-specific multivariable modules as described above. We used SAS Version 9.3 (SAS Institute, Cary NC).

Results The mean (SD) height for mothers was 165.1 cm (6.9) and 179.4 cm (7.7) for fathers (Table 1). Mothers were 32.3 years old (5.0) at their first prenatal visit, and pre-pregnancy BMI was 24.8 kg/m2 (5.3). Of the children included in the study, 711 (51%) of 1395 were male and 684 (49%) were female. Mean (SD) femur length at 2nd trimester ultrasound was 26.9 mm (3.2). Lengths/heights at birth, 6 months, early childhood (median 3.2 years) and mid-childhood (median 7.7 years) were 49.8 cm (2.1), 66.8 cm (2.7), 97.5 cm (4.7), and 128.4 cm (7.7), respectively. Based on absolute heights, male children were slightly taller than female children at all time points. Mean (SD) length/height z-scores for children in this study at the same time intervals, based on CDC reference data, were -0.01 (0.84), -0.08 (0.90), 0.25 (0.94), and 0.24 (0.99) units, respectively (Table 1). These data demonstrate that children in our cohort are similar in length in infancy to children from around the , but they are somewhat taller by early childhood. There was no consistent correlation between male and female height z- scores. Our outcomes of interest were height or length change in z-scores from one age to the next. These change values were -0.01 (1.17) from 2nd trimester to birth, -0.05 (0.81) from birth to infancy, 0.33 (0.76) from 6 months to early childhood, and -0.02 (0.47) from early to mid- childhood (Table 1). Mothers’ and fathers’ heights were moderately correlated with each other (Pearson r = 0.18). Maternal pre-pregnancy BMI was slightly lower across higher quartiles of maternal height, from 25.0 kg/m2 (5.6) to 24.8 (4.9), 24.7 (5.3), and 24.6 (5.1) (Supplemental Table 1). Hispanic and Asian mothers tended to be shorter; 53 of 83 Hispanic mothers and 50 of 69 Asian mothers fell into the shorter two quartiles. Femur length measured at 2nd trimester was higher across the 2nd-4th paternal height quartiles, but was fairly unchanged across maternal height quartiles. We first performed multivariable regression analysis for males and females combined (Table 2) and then stratified by offspring sex (Figure 1). There were no significant differences between the associations of maternal versus paternal height with change in offspring length/height z-score (p=0.06). The magnitude of associations of both maternal and paternal height with change in offspring height were similar over the first 3 growth periods (maternal 0.14, 0.10, 0.16 and paternal 0.11, 0.12, 0.13, in chronologic order). Estimates dropped off during the early to mid-childhood growth period with a 1 unit z-score increment in maternal height associated with a 0.07 (95% CI 0.04, 0.10) unit change in offspring height z-score, with a similar estimate of 0.06 (95% CI 0.03, 0.09) for paternal height (Table 2, Model 2). In the sex-stratified analyses, the association of maternal height with change in offspring length from 2nd trimester femur length to birth length was 0.21 (95% CI 0.11, 0.31) among females versus 0.10 (0.03, 0.18) among males (interaction p-value 0.07). Also, the association of paternal height with change in offspring height from early to mid-childhood was 0.09 (0.05, 0.14) among females versus 0.03 (-0.01, 0.07) among males (interaction p-value 0.04). All other associations were similar among females versus males (Figure 1). When comparing maternal and paternal height associations at each age interval, the greatest differential observed was change in female offspring length z-score from 2nd trimester femur length to birth length, with an effect estimate of 0.21 (95% CI 0.11, 0.31) for maternal height versus 0.08 (95% CI -0.01, 0.17) for paternal height (Figure 1); this represents a difference of 0.13 (95% CI 0.00, 0.26, p=0.05). All other differences were subtler.

Discussion, Limitations, Conclusions We demonstrated that that the influence of both mother’s and father’s height on offspring linear growth was greatest prenatally and in postnatal growth periods before 3 years of age, and diminished in magnitude between 3 and 7 years of age. We also showed that linear growth of female was more strongly associated with maternal than paternal height, after adjusting for other parental factors that could influence fetal linear growth, including race/ethnicity and maternal pre-pregnancy BMI. No prior studies of in utero linear growth have examined growth beyond 3 years of age, and none have examined influences of parental factors on sex-specific offspring lengths. Our finding of strong parent-offspring height associations before 3 years of age expands findings of at least one other study. Mook-Kanamori et al.’s Generation R and Netherland Twin Register cohort analysis demonstrated a height heritability estimate increase of 13% to 28% from 2nd to 3rd trimester, with more gradual but continued increases in heritability through 3 years of age (to 63%). This study did not continue past 3 years. [11]. The infancy-childhood-puberty (ICP) model, which describes how child linear growth is regulated at different stages in development, may help explain why we see a decrement in the association of parental height with child linear growth after 3 years, despite the fact that may explain more of a child’s height growth with age, at least after 1 year [22]. From 3 to 10 years, linear growth is primarily determined by growth hormone (GH) [23]. Paternoster et al.[22] showed that prior to this period, HHIP, a involved in the hedgehog signal transduction pathway and known to play a role in development during infancy, is associated with growth from years 1-3. They then reported that the height-related variant SOCS2, was associated with child linear growth between 3 and 10 years. Other studies have demonstrated that production of SOCS proteins is stimulated by GH, and that SOCS2 then goes on to regulate GH signaling [24]. Leung et al.[25] demonstrated involvement of steroid hormones in GH expression, showing that GH signaling is down- regulated by , but only in the presence of SOCS2. Therefore, while SOCS2 variants are shared by parents and offspring and represent a particular height/growth potential, GH expression is also regulated by non-parental factors, such as sex hormones. So, while early infancy growth may be largely controlled by parental height-related variants like HHIP, GH- mediated growth after 3 years of age has some degree of hormonal regulation, potentially explaining the diminishing association of parental height with offspring linear growth we observed during mid-childhood. Our novel finding of a maternal-daughter link during in utero growth may be explained by differences in male and female placentas. A study done in Saudi Arabia first demonstrated that birth length was associated with placental breadth [26]. A second study, in a different Saudi Arabian cohort, similarly demonstrated an association between birth length and placental breadth, and also stratified results by offspring sex. Female offspring birth length was found to be more strongly associated with placental breadth (r=0.30) than was male birth length (r=0.22) [27]. Placental breadth may respond to changes in maternal nutrient availability, with increasing breadth representing increased trans-placental nutrient transfer [26,28]. Taller mothers have increased rates of protein metabolism during pregnancy, assessed using oral [15N] glycine and the end-product method, and this increased protein metabolism was also shown to predict increased birth length [29]. Indeed, Alwasel et al. were able to show that taller mothers (>157 cm) demonstrated a 0.30 cm increment in birth length for every 1 cm increase in placental breadth (p=0.004), while shorter mothers had an increment of only 0.19 cm (p=0.08) [26]. Given the female greater than male association of placental breadth with birth length, and the nutrient regulation of growth along the minor placental axis (breadth), the increased protein turnover in taller mothers may represent the link underlying the stronger association between maternal height and daughter linear growth in utero. Strengths of this study include prospective data collection and use of length/height measurements from both the prenatal and childhood growth periods. Another strength is use of length/height change variables instead of static height measures. Catch-up and catch-down linear growth during the first 6 months of life, quantified by Karlberg and others [30-32], describes the tendency of infant length to converge toward the mean height for age over the first 6 months of life. Adjusting for the child’s length/height at birth, at 6 months, and at the beginning of the other two growth interval, helps to overcome regression to the mean as a result of such changes. Limitations of this study include the use of clinical ultrasound data to measure femur length, and femur length from only one point in pregnancy (early 2nd trimester). Femur length can be used as a proxy for linear growth in utero [33], so it would have been helpful to have a second femur length measurement to better assess growth trajectory through different periods in pregnancy. We do not know if our maternally-reported paternal heights are overestimated, as reported by Braziuniene et al.[19]. The authors of that study, however, did not evaluate rank- ordering of maternally-reported paternal heights; a uniform overestimation would have had little effect on our analysis. Lastly, because the participants were primarily from non-low income families in a , the findings may not be generalizable to other settings. This study had two main findings. First, the impact of parental height on child linear growth rates diminished after the preschool years. This result suggests that factors that arise during childhood, for example variation in growth hormone secretion, may become more important than parents’ early influence as children become older. Second, we found a strong association of maternal height with daughter linear growth in utero, which could represent differential regulation of placental growth in taller mothers, leading to female greater than male in utero growth. Other studies should search to replicate, and explain, these novel findings.

Acknowledgments I would like to acknowledge my mentor, Dr. Matthew Gillman, for his support throughout this project. Also, Sheryl Rifas-Shiman was an invaluable resource in orienting me to SAS, working through the statistical analysis, and offering suggestions throughout the project. This work was supported by the National Institutes of Health under Grant R37 HD 034568; Harvard Pilgrim Health Care; and Harvard Medical School’s Scholars in Medicine program.

References [1] Silventoinen K, Sammalisto S, Perola M, et al. Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res. 2003;6:399-408. [2] Perola, M, Sammalisto S, Hiekkalinna T, et al. Combined genome scans for body status in 6,602 European Twins: Evidence for Common Caucasian Loci. Abecasis G, ed. PLoS Genet. 2007 Jun;3(6):e97. [3] Altshuler D, Brooks LD, Chakravarti A, et al. A haplotype map of the human genome. . 2005;437:1299-1320. [4] Lango Allen H, Estrada K, Lettre G et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010;467(7317):832-838. [5] Nelson CP, Hamby SE, Saleheen D, et al. Genetically determined height and coronary artery disease. N Engl J Med. 2015 Apr 23;372(17):1608-18. [6] Davey Smith G, Hart C, Upton M, et al. Height and risk of death among men and women: aetiological implications of association with cardiorespiratory disease and cancer mortality. J Epidemiol Commun H. 2000;54:97-103. [7] Jousilahti P, Tuomilehto J, Vartiainen E, et al. Relation of adult height to cause-specific and total mortality: a prospective follow-up study of 31,199 middle-aged men and women in Finland. Am J Epidemiol. 2000;151:1112-1120. [8] Song Y, Sung J. Adult height and the risk of mortality in South Korean women. Am J Epidemiol. 2008; 168:497-505. [9] Gunnell D, Okasha M, Davey Smith G, et al. Height, leg length, and cancer risk: a systematic review. Epidemiol Rev. 2001;23:313-342. [10] Regnault N, Kleinman KP, Rifas-Shiman SL, et al. Components of height and blood pressure in childhood. International Journal of Epidemiology. 2014;43(1):149-159. doi:10.1093/ije/dyt248. [11] Mook-Kanamori DO, van Beijsterveldt CE, Steegers EAP, et al. Heritability Estimates of Body Size in Fetal Life and Early Childhood. PLoS One. 2012;7(7):e39901. [12] Albouy-Llaty M, Thiebaugeorges O, Goua V, et al. Influence of fetal and parental factors on intrauterine growth measurements: results of the EDEN mother-child cohort. Ultrasound Obstet Gynecol. 2011;38:673-680 [13] Knight B, Shields BM, Turner M, et al. Evidence of genetic regulation of fetal longitudinal growth. Early Hum Dev. 2005;81(10):823-31. [14] Tandon N, Fall CHD, Osmond C, et al. Growth from birth to adulthood and peak bone mass and density data from the new Delhi Birth Cohort. Osteoporos Int. 2012; 23:2447- 2459. [15] Wills AK, Chinchwadkar MC, Joglekar CV, et al. Maternal and paternal height and BMI and patterns of fetal growth: The Pune Maternal Nutrition Study. Early Hum Dev. 2010; 86(9):535-540. [16] Oken E, Baccarelli AA, Gold DR, et al. Cohort profile: project viva. Int J Epidemiol. Feb 2015;44(1):37-48. [17] Lin CJ, DeRoo LA, Jacobs SR, et al. Accuracy and reliability of self-reported weight and height in the Sister Study. Public Health Nutr. 2012 Jun; 15(6):989-999. [18] Paez KA, Griffey SJ, Thompson J, et al. Validation of self-reported weights and heights in the avoiding diabetes after pregnancy trial (ADAPT). BMC Med Res Methodol. 2014;14:65. [19] Braziuniene I, Wilson TA, Lane AH, et al. Accuracy of self-reported height measurements in parents and its effect on mid-parental target height calculation. BMC Endocrine Disorders. 2007;7:2. [20] Parker M, Rifas-Shiman SL, Oken E, et al. Second Trimester Estimated Fetal Weight and Fetal Weight Gain Predict Childhood Obesity. J Pediatrics. 2012;161(5):864-870. [21] National Center for Health Statistics. CDC Growth Charts, United States. 2000. Available at: http://www.cdc.gov/growthcharts/. [22] Paternoster L, Howe LD, Tilling K, et al. Adult height variants affect birth length and growth rate in children. Hum Mol Genet. 2011;20:4069-4075. [23] Tse WY, Hindmarsh PC, Brook CG. The infancy-childhood-puberty model of growth: clinical aspects. Acta Paediatr Scand Suppl. 1989;356:38-43. [24] Greenhalgh CJ, Alexander WS. Suppressors of cytokine signaling and regulation of growth hormone action. Growth Horm IGF Res. 2004;14:200–206. [25] Leung KC, Doyle N, Ballesteros M, et al. inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Proc Natl Acad Sci U S A. 2003;100:1016–1021. [26] Alwasel SH, Abotalib Z, Aljarallah JS, et al. The breadth of the placental surface but not the length is associated with body size at birth. Placenta. 2012 Aug;33(8):619-22. [27] Alwasel SH, Harrath AH, Aldahmash WM, et al. Sex differences in regional specialisation across the placental surface. Placenta. 2014 Jun;35(6):365-9. [28] Kajantie E, Thornburg K, Eriksson JG, et al. In preeclampsia, the placenta grows slowly along its minor axis. Int J Dev Biol. 2010;54:469–473. [29] Duggleby SL, Jackson AA. Relationship of maternal protein turnover and lean body mass during pregnancy and birth length. Clinical Science. 2001 Jul;101(1):65-72. [30] Karlberg J, Albertsson-Wikland K, Kwan CW, et al. Early spontaneous catch-up growth. J Pediatr Endocrinol Metab. 2002 Dec;15 Suppl5:1243-55. [31] Karlberg J and Luo ZC. Foetal size to final height. Acta Paeditr. 2000;89:632-6. [32] Luo ZC, Albertsson-Wikland K, Karlberg J. Length and Body Mass Index at Birth and Target Height Influences on Patterns of Postnatal Growth in Children Born Small for Gestational Age. Pediatrics. 1998;102(6):E72. [33] Hadlock FP, Deter RL, Roecker E, et al. Relation of fetal femur length to neonatal crown-heel length. J Ultrasound Med. 1984 Jan;3(1):1-3.

Table 1: Characteristics of 1395 mother/father/offspring triads in Project Viva, with stratification into 684 female and 711 male offspring. Results are listed as mean (SD) or number (%).

Total Females Males

n=1395 n=684 n=711

Maternal characteristics

Height, cm 165.1 (6.9) 164.8 (6.8) 165.3 (7.0)

Age, years 32.3 (5.0) 32.6 (4.8) 32.0 (5.3)

Pre-pregnancy BMI, kg/m2 24.8 (5.3) 24.6 (5.3) 24.9 (5.2)

College graduate (%)

No 422 (30.3) 182 (26.6) 240 (33.8)

Yes 973 (69.7) 502 (73.4) 471 (66.2)

Married or cohabitating (%)

No 98 (7.0) 48 (7.0) 50 (7.0)

Yes 1297 (93.0) 636 (93.0) 661 (93.0)

Nulliparous (%)

No 710 (50.9) 342 (50.0) 368 (51.8)

Yes 685 (49.1) 342 (50.0) 343 (48.2)

Pregnancy smoking status (%)

Never 964 (69.4) 484 (71.2) 480 (67.6)

Former 279 (20.1) 133 (19.6) 146 (20.6)

During pregnancy 147 (10.6) 63 (9.3) 84 (11.8)

Race/ethnicity (%)

Black 192 (13.8) 87 (12.7) 105 (14.8)

Hispanic 83 (5.9) 35 (5.1) 48 (6.8)

Asian 69 (4.9) 33 (4.8) 36 (5.1)

White 993 (71.2) 501 (73.2) 492 (69.2)

Other 58 (4.2) 28 (4.1) 30 (4.2) Total Females Males

Paternal height, cm 179.4 (7.7) 179.6 (7.6) 179.2 (7.8)

Household income at enrollment >$70,000/y (%)

No 470 (36.3) 234 (36.3) 236 (36.3)

Yes 824 (63.7) 410 (63.7) 414 (63.7)

Child characteristics

Female (%)

No 711 (51.0) 0 (0.0) 711 (100)

Yes 684 (49.0) 684 (100) 0 (0.0)

Race/ethnicity (%)

Black 198 (14.2) 89 (13.0) 109 (15.3)

Hispanic 57 (4.1) 18 (2.6) 39 (5.5)

Asian 49 (3.5) 26 (3.8) 23 (3.2)

White 939 (67.3) 476 (69.6) 463 (65.1)

Other 152 (10.9) 75 (11.0) 77 (10.8)

GA at birth, weeks 39.6 (1.7) 39.6 (1.6) 39.5 (1.8)

Birthweight, grams 3501 (542) 3440 (501) 3561 (573)

Birthweight for GA, z-score 0.21 (0.96) 0.20 (0.94) 0.21 (0.98)

Femur length, mm 26.9 (3.2) 26.8 (3.1) 27.0 (3.3)

GA-adj femur length, internal z-score 0.00 (1.00) 0.00 (1.00) 0.00 (1.00)

Length at birth, cm 49.8 (2.1) 49.4 (2.1) 50.2 (2.1)

Length at birth, z-score -0.01 (0.84) -0.05 (0.87) 0.02 (0.80)

Length in infancy (6 months), cm 66.8 (2.7) 65.9 (2.5) 67.6 (2.6)

Length in infancy (6 months), z-score -0.08 (0.90) -0.05 (0.87) -0.11 (0.94)

Height in early childhood (~3 years), cm 97.5 (4.7) 96.8 (4.5) 98.1 (4.8)

Height in early childhood (~3 years), z-score 0.25 (0.94) 0.26 (0.89) 0.23 (0.98)

Height in mid-childhood (~7 years), cm 128.4 (7.7) 128.1 (7.8) 128.7 (7.5) Total Females Males

Height in mid-childhood (~7 years), z-score 0.24 (0.99) 0.20 (0.96) 0.28 (1.02)

Change in z-score 2nd trimester to birth -0.01 (1.17) -0.01 (1.14) -0.00 (1.20)

Change in z-score birth to infancy -0.05 (0.81) 0.01 (0.86) -0.11 (0.76)

Change in z-score infancy to early childhood 0.33 (0.76) 0.29 (0.73) 0.37 (0.78)

Change in z-score early to mid-childhood -0.02 (0.47) -0.10 (0.47) 0.05 (0.46)

BMI: body mass index GA: gestational age Table S1: Characteristics of 1395 mother/father/offspring triads in Project Viva, stratified by quartiles of maternal and paternal height.

Quartiles of maternal height Quartiles of paternal height Quartile 1 2 3 4 1 2 3 4 N 407 216 359 413 350 344 335 366 Maternal characteristics Height, cm 157.0 (3.5) 162.6 (0.0) 166.4 (1.3) 173.3 (3.5) 163.1 (6.4) 165.0 (6.7) 165.9 (7.1) 166.3 (7.1) Age, years 31.8 (5.2) 32.5 (5.1) 32.4 (4.8) 32.6 (5.1) 31.5 (5.5) 32.6 (5.2) 32.7 (4.7) 32.5 (4.7) Pre-pregnancy BMI, kg/m2 25.0 (5.6) 24.8 (4.9) 24.7 (5.3) 24.6 (5.1) 25.5 (5.9) 24.8 (5.2) 23.9 (4.6) 24.7 (5.1) College graduate (%) No 133 (32.7) 66 (30.6) 103 (28.7) 120 (29.1) 136 (38.9) 101 (29.4) 78 (23.3) 107 (29.2) Yes 274 (67.3) 150 (69.4) 256 (71.3) 293 (70.9) 214 (61.1) 243 (70.6) 257 (76.7) 259 (70.8) Married or cohabitating (%) No 33 (8.1) 13 (6.0) 21 (5.8) 31 (7.5) 35 (10.0) 25 (7.3) 12 (3.6) 26 (7.1) Yes 374 (91.9) 203 (94.0) 338 (94.2) 382 (92.5) 315 (90.0) 319 (92.7) 323 (96.4) 340 (92.9) Nulliparous (%) No 194 (47.7) 105 (48.6) 188 (52.4) 223 (54.0) 182 (52.0) 167 (48.5) 173 (51.6) 188 (51.4) Yes 213 (52.3) 111 (51.4) 171 (47.6) 190 (46.0) 168 (48.0) 177 (51.5) 162 (48.4) 178 (48.6) Pregnancy smoking status (%) Never 293 (72.3) 158 (73.1) 241 (67.3) 272 (66.2) 254 (72.8) 242 (70.3) 215 (64.6) 253 (69.5) Former 71 (17.5) 37 (17.1) 77 (21.5) 94 (22.9) 54 (15.5) 69 (20.1) 87 (26.1) 69 (19.0) During pregnancy 41 (10.1) 21 (9.7) 40 (11.2) 45 (10.9) 41 (11.7) 33 (9.6) 31 (9.3) 42 (11.5) Race/ethnicity (%) Black 52 (12.8) 32 (14.8) 53 (14.8) 55 (13.3) 70 (20.0) 37 (10.8) 33 (9.9) 52 (14.2) Hispanic 38 (9.3) 15 (6.9) 13 (3.6) 17 (4.1) 37 (10.6) 15 (4.4) 14 (4.2) 17 (4.6) Asian 43 (10.6) 7 (3.2) 10 (2.8) 9 (2.2) 30 (8.6) 12 (3.5) 11 (3.3) 16 (4.4) White 260 (63.9) 157 (72.7) 267 (74.4) 309 (74.8) 201 (57.4) 261 (75.9) 268 (80.0) 263 (71.9) Other 14 (3.4) 5 (2.3) 16 (4.5) 23 (5.6) 12 (3.4) 19 (5.5) 9 (2.7) 18 (4.9) Paternal height, cm 177.6 (7.8) 178.8 (8.0) 179.5 (7.8) 181.3 (6.9) 169.4 (3.5) 176.8 (1.2) 181.7 (1.3) 189.0 (3.7) Household income at enrollment >$70,000/y (%) No 146 (39.1) 74 (37.0) 114 (34.1) 136 (35.1) 147 (45.8) 111 (35.0) 97 (30.6) 115 (33.9) Yes 227 (60.9) 126 (63.0) 220 (65.9) 251 (64.9) 174 (54.2) 206 (65.0) 220 (69.4) 224 (66.1)

Child characteristics Female, % No 194 (47.7) 112 (51.9) 186 (51.8) 219 (53.0) 190 (54.3) 168 (48.8) 165 (49.3) 188 (51.4) Yes 213 (52.3) 104 (48.1) 173 (48.2) 194 (47.0) 160 (45.7) 176 (51.2) 170 (50.7) 178 (48.6) Race/ethnicity (%) Black 55 (13.5) 31 (14.4) 50 (13.9) 62 (15.0) 69 (19.7) 38 (11.0) 31 (9.3) 60 (16.4) Hispanic 30 (7.4) 12 (5.6) 7 (1.9) 8 (1.9) 31 (8.9) 12 (3.5) 9 (2.7) 5 (1.4) Asian 30 (7.4) 4 (1.9) 6 (1.7) 9 (2.2) 28 (8.0) 8 (2.3) 6 (1.8) 7 (1.9) White 244 (60.0) 148 (68.5) 256 (71.3) 291 (70.5) 184 (52.6) 249 (72.4) 257 (76.7) 249 (68.0) Other 48 (11.8) 21 (9.7) 40 (11.1) 43 (10.4) 38 (10.9) 37 (10.8) 32 (9.6) 45 (12.3) GA at birth, weeks 39.4 (1.9) 39.6 (1.7) 39.8 (1.7) 39.6 (1.5) 39.4 (1.9) 39.6 (1.6) 39.8 (1.5) 39.6 (1.8) Birthweight, gm 3363 (549) 3420 (515) 3566 (518) 3624 (534) 3395 (575) 3494 (522) 3579 (492) 3539 (558) Birthweight/GA z-score -0.03 (0.96) 0.03 (0.91) 0.30 (0.90) 0.45 (0.96) 0.02 (0.97) 0.19 (0.97) 0.33 (0.91) 0.28 (0.96) Femur length, mm 26.8 (3.4) 26.8 (3.1) 26.8 (3.2) 27.3 (2.9) 26.8 (3.2) 26.8 (3.0) 27.0 (3.0) 27.2 (3.5) GA-adj femur length, internal z- -0.13 (1.09) 0.04 (1.01) 0.02 (1.01) 0.10 (0.87) -0.05 (1.10) -0.08 (0.90) 0.06 (0.91) 0.07 (1.08) score Length at birth, cm 49.3 (2.1) 49.6 (2.0) 50.1 (2.0) 50.2 (2.2) 49.3 (2.2) 49.6 (2.2) 50.2 (1.9) 50.1 (2.1) Length at birth, z-score -0.23 (0.84) -0.11 (0.77) 0.11 (0.80) 0.14 (0.86) -0.21 (0.90) -0.08 (0.87) 0.15 (0.71) 0.10 (0.83) Length in infancy (6 mo), cm 66.1 ( 2.5) 66.2 ( 2.7) 67.1 ( 2.7) 67.5 ( 2.6) 66.1 ( 2.7) 66.5 ( 2.4) 67.0 ( 2.5) 67.4 ( 2.9) Length in infancy (6 mo), z-score -0.31 (0.86) -0.35 (0.96) 0.05 (0.87) 0.17 (0.86) -0.35 (0.94) -0.18 (0.80) 0.04 (0.80) 0.15 (0.98) Height early childhood (~3 yrs), 95.8 (4.5) 97.4 (5.1) 97.7 (4.3) 98.9 (4.5) 96.8 (5.2) 96.7 (4.3) 97.2 (4.3) 99.0 (4.5) cm Height early childhood (~3 yrs), -0.12 (0.96) 0.15 (0.86) 0.29 (0.83) 0.61 (0.89) -0.03 (0.90) 0.07 (0.86) 0.26 (0.93) 0.65 (0.91) z-score Height mid-childhood (~7 years), 125.8 (7.8) 127.6 (7.3) 129.0 (7.1) 130.8 (7.3) 126.2 (7.1) 127.1 (7.3) 128.8 (7.3) 131.3 (7.9) cm Height mid-childhood (~7 years), -0.18 (1.01) 0.17 (0.89) 0.26 (0.90) 0.64 (0.93) -0.09 (0.98) 0.03 (0.95) 0.29 (0.93) 0.68 (0.93) z-score Change in z-score 2nd trimester to -0.15 (1.20) -0.16 (1.28) 0.07 (1.14) 0.16 (1.09) -0.28 (1.11) -0.00 (1.18) 0.18 (1.03) 0.05 (1.30) birth Change in z-score birth to infancy -0.01 (0.78) -0.19 (0.76) -0.04 (0.74) -0.03 (0.92) -0.08 (0.97) -0.08 (0.77) -0.10 (0.72) 0.06 (0.78) Change in z-score infancy to early 0.22 (0.75) 0.44 (0.75) 0.26 (0.72) 0.45 (0.78) 0.29 (0.79) 0.28 (0.66) 0.28 (0.73) 0.47 (0.83) childhood Change in z-score early to mid- -0.10 (0.46) -0.01 (0.47) -0.02 (0.48) 0.04 (0.47) -0.09 (0.51) -0.04 (0.45) 0.02 (0.45) 0.01 (0.47) childhood

BMI: body mass index GA: gestational age

Table 2: Associations of maternal and paternal height (per internal z-score) with change in offspring length or height z-score (male and female offspring combined). Data is from 1395 mother/father/offspring triads in Project Viva, all of whom are represented in one or more of the change in length/height intervals shown below.

Outcome Exposure Model 0 Model 1 Model 2

Change in length or height z-score Height z-score N Estimate (95% CI)

Mother 0.12 (0.01, 0.22) 0.17 (0.10, 0.23) 0.14 (0.09, 0.20) 2nd trimester (femur length) to birth 563 Father 0.10 (0.01, 0.20) 0.12 (0.05, 0.18) 0.11 (0.05, 0.16)

Mother 0.01 (-0.05, 0.08) 0.10 (0.05, 0.16) 0.10 (0.04, 0.15) Birth to infancy (~6 months) 699 Father 0.02 (-0.04, 0.09) 0.09 (0.04, 0.14) 0.12 (0.06, 0.18)

Mother 0.07 (0.03, 0.12) 0.15 (0.11, 0.20) 0.16 (0.11, 0.20) Infancy to early childhood (~3 years) 922 Father 0.05 (0.00, 0.10) 0.11 (0.07, 0.16) 0.13 (0.08, 0.18)

Mother 0.04 (0.01, 0.07) 0.07 (0.04, 0.10) 0.07 (0.04, 0.10) Early to mid-childhood (~7 years) 958 Father 0.03 (0.00, 0.06) 0.06 (0.03, 0.09) 0.06 (0.03, 0.09)

Model 0: Adjusted for child sex

Model 1. Model 0 + starting length z-score of change outcome

Model 2. Model 1 + gestational age at birth, maternal pre-pregnancy BMI, smoking during pregnancy, household income and child race/ethnicity

Figure Legends

Figure 1 Associations of maternal and paternal height z-scores with offspring length/height change, estimated as change in z-score over each of four different age periods: 2nd trimester to birth, birth to infancy (6 months), infancy to early childhood (median 3.2 years), and early to mid-childhood

(median 7.7 years) per increment of parent height z-score. Results stratified by offspring sex.

Linear regression estimates (95% CI) adjusted for maternal pre-pregnancy BMI, smoking during pregnancy and household income, and child race/ethnicity, starting length z-score at each age period and gestational age at birth. Data from 684 female (A) and 711 male (B) offspring in

Project Viva.

26 A

Female offspring 0.35 Mother 0.30 Father

0.25

0.20

0.15

0.10

0.05

0.00

-0.05 2nd trim - birth Birth - 6m 6m - early childhood Early - mid-childhood

B Male offspring 0.35 Mother 0.30 Father

0.25

0.20

0.15

0.10

0.05

0.00

-0.05 2nd trim - birth Birth - 6m 6m - early childhood Early - mid-childhood

27