association of infant physical development and rapid growth ......introduction...

Original Investigation | Pediatrics

Association of Infant Physical Development and Rapid GrowthWith Pubertal Onset Among Girls in Rural ChinaJing Wei, BSc; Shuang Liu, BSc; Yue Cheng, PhD; Wenfang Yang, PhD; Zhonghai Zhu, PhD; Lingxia Zeng, PhD

Abstract

IMPORTANCE Whether physical development and rapid growth during the first 2 years of life areassociated with puberty onset in girls remains unclear.

OBJECTIVE To examine the associations of infant physical development and rapid growth with thetiming of puberty onset in girls.

DESIGN, SETTING, AND PARTICIPANTS This prospective birth cohort study included girls whosemothers had participated in a randomized, double-blind cluster trial of micronutrientsupplementation with a daily capsule of folic acid, iron and folic acid, or multiple micronutrientsduring pregnancy. A total of 547 singleton girls in rural western China who were born after 2004were followed up at 3, 6, 12, and 24 months of age and were eligible for long-term follow-up. Ofthese, 294 adolescent girls (aged 10-12 years), representing 53.7% of the total sample, were includedin the follow-up interview that was conducted from June 1 through December 31, 2016. Data analyseswere conducted from November 1, 2019, to May 30, 2020.

EXPOSURES Infant weight and length were assessed at birth and 3, 6, 12, and 24 months of age.Rapid growth, defined as a weight-for-age or length-for-age z score increase of greater than 0.67, wascalculated during 5 periods: birth to 3 months, birth to 6 months, 6 to 12 months, 12 to 24 months,and birth to 24 months of age.

MAIN OUTCOMES AND MEASURES Puberty stage was assessed using the standardized Tannerstaging system. Onset of puberty was defined as attaining Tanner stage 2 of breast development orpubic hair growth, and the corresponding age at follow-up was recorded.

RESULTS Of 294 girls included in the analysis (mean [SD] age, 11.25 [0.57] years), the median age ofpuberty onset was 11 (interquartile range, 10-11) years. A significant association with puberty onsetwas found for infancy weight-for-age z score at 12 months of age (adjusted hazard ratio [HR], 1.20;95% CI, 1.01-1.44) and rapid weight gain from birth to 24 months of age (adjusted HR, 1.40; 95% CI,1.01-1.93) and birth to 3 months of age (adjusted HR, 1.39; 95% CI, 1.02-1.91). However, length-related indicators during early life were not associated with adolescent puberty onset.

CONCLUSIONS AND RELEVANCE This study found that a higher weight-for-age z score and rapidweight gain during infancy, particularly from birth to 3 months of age, were associated with anincreased likelihood of puberty onset in girls. These findings suggest that weight-related indicatorsmay serve as proxies of puberty onset among adolescent girls.

JAMA Network Open. 2021;4(5):e216831. doi:10.1001/jamanetworkopen.2021.6831

Key PointsQuestion What is the long-term

association of infant physical

development and rapid growth with the

timing of puberty onset in girls?

Findings In this birth cohort of 294

adolescent girls in rural China, the

infancy weight-for-age z score at 12

months of age and rapid weight gain

from birth to 24 months of age and birth

to 3 months of age were associated with

puberty onset.

Meaning The findings suggest that

weight-related indicators may serve as

proxies of puberty onset among

adolescent girls.

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Introduction

Growing evidence indicates that puberty onset has been occurring at an earlier age in girls.1,2 Thismay increase the risk of diseases in adulthood, such as breast, ovarian, and endometrial cancers,metabolic syndrome, and cardiovascular disease.3,4 A worldwide meta-analysis1 concluded that ageat puberty onset among girls has decreased by approximately 3 months per decade from 1977to 2013.

The literature to date has largely focused on secular increases in body mass index (BMI) in earlychildhood and their associations with the timing of puberty (ie, menarche and puberty onset),5 withhigher BMI in childhood associated with earlier puberty.6,7 It remains unclear whether body sizeduring the first 2 years of life, a critical window that lays the foundation for long-term healthoutcomes, is also associated with puberty. A systematic review based on cohort studies8 reportedthat small for gestational age (SGA) and low birth weight (LBW) were associated with earlier age atpuberty onset in girls (weighted mean difference, 0.64; 95% CI, 1.21-0.06). Few studies havedetailed measures of weight and height during childhood,9 and these studies lacked specific seculardata during the first 2 years of life. Infant rapid growth, compensating for intrauterine growthrestriction, is usually observed during the first 2 years after birth.10 Emerging evidence suggests thatthe timing of rapid growth (tempo) itself may play an independent role in modifying subsequenthealth outcomes.11 However, it is not clear which period of rapid growth during infancy results inearlier puberty. Few studies have examined the association of rapid weight gain in infancy withpuberty, and limited assessments have been performed.12,13 The DONALD (Dortmund Nutritionaland Anthropometric Longitudinally Designed) Study from Germany12 assessed rapid weight gainwith measurements at birth and at 24 months of age. Another birth cohort from South Africa focusedon transient rapid weight gain from birth to 12 months of age.13 Thus, a study with multipleprospective measures of growth during the first 2 years of life is needed to determine the specificperiod associated with the timing of puberty.

To assess puberty onset, previous studies9,14 have mainly used the timing of menarche, arelatively late milestone of pubertal development, which may mask the true associations of infantgrowth in early life with puberty onset. In addition, growth during early life may interfere with theonset of puberty but not the subsequent stages or durations (ie, the timing of menarche).12

In the present study, we aimed to investigate the associations of infant physical developmentand rapid growth during early life with puberty onset in girls. We used birth cohort data in ruralwestern China, with physical development (weight, length, and rapid growth) assessed at birth andat 3, 6, 12, and 24 months of age and puberty assessment at early adolescence (10-12 years of age).Our results may help to identify the strongest indicator of physical development that is associatedwith puberty onset and its critical period within the first 2 years after birth.

Methods

Study Design and ParticipantsThe study design was a prospective birth cohort of participants whose mothers participated in arandomized, double-blind cluster trial of micronutrient supplementation in pregnancy.15 The parenttrial is detailed elsewhere.16 Briefly, pregnant women in the designated villages were randomlyallocated to daily supplementation with folic acid (400 μg [control group]), iron (60 mg) and folicacid (400 μg), or multiple micronutrients in accordance with the World Health Organization’srecommended allowance of 15 vitamins and minerals; supplements were used from enrollment todelivery.17 In the trial, 4604 singleton births occurred, but only 1400 births in 2004-2006 wereenrolled in the long-term follow-up cohort. A total of 1388 births were followed up after excludingdeaths (n = 3), children with birth defects (n = 7), and parents with disabilities (n = 2). Among them,547 girls were eligible for long-term follow-up. Finally, we tracked 294 girls (53.7%) from birth

JAMA Network Open | Pediatrics Association of Infant Physical Development and Rapid Growth With Pubertal Onset in Girls



through 3, 6, 12, and 24 months of age and into early adolescence (10-12 years of age). Follow-up datawere collected from June 1 through December 31, 2016.

The follow-up evaluations were approved by the ethics committee of the Xi’an JiaotongUniversity Health Science Center in Xi’an, China. Parents or caregivers provided signed informedconsent, and verbal assent was obtained from each child. This study followed the Strengthening theReporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Anthropometric MeasurementsWeight and Linear GrowthBirth weight and length were measured by the nursing staff within 1 hour of delivery at the hospital(263 [89.5%]) or by township maternal and child health care staff within 72 hours for home deliveries(31 [10.5%]). Weight and length at 3, 6, 12, and 24 months of age at each follow-up visit weremeasured using standard World Health Organization procedures. Weight was measured to thenearest 10 g using an electronic scale (type BD-585; Tanita Corporation) after removing heavyclothes. Length was measured to the nearest 1 mm using a portable measuring board with a fixedheadpiece.

Low birth weight was defined as less than 2500 g. Body mass index was calculated as weight inkilograms divided by the square of body height in meters. The infant weight-for-age z score (WAZ),length-for-age z score (LAZ), and BMI-for-age z score (BAZ) were calculated using the World HealthOrganization Child Growth Standards 2006.18 The birth WAZ and LAZ were accordingly calculatedby International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st)standards.19 Infant stunting was defined as an LAZ less than −2.00 SD; underweight, an WAZ lessthan −1.00 SD; and overweight, a BAZ greater than 2.00 SD.20,21

Changes in z scores among infants were calculated using WAZ or LAZ at the end minus thescores at the beginning of every interval of interest, including birth to 3 months of age, birth to 6months of age, 6 to 12 months of age, 12 to 24 months of age, and birth to 24 months of age. Wedefined rapid growth as a change in z score that was greater than 0.67.22

Pubertal DevelopmentTrained public health postgraduate students (including Z.Z.) measured the staging of breastdevelopment using observation and palpation according to the Tanner staging system, whichrepresents the 5 Tanner stages for breast size. Similarly, the development of pubic hair was staged byvisual inspection. We defined the onset of puberty as attaining Tanner stage 2 of breast developmentor pubic hair growth.23,24 Among girls with a Tanner stage greater than 2 (68 [23.1%]), the age ofpuberty onset was determined by asking the following questions: (1) Have you noticed that yourbreasts/pubic hair have begun to grow? (2) If yes, how old were you when this began? As for othergirls with a Tanner stage of 2 (173 [58.8%]), we used the chronological age at visit as the age ofpuberty onset.

CovariablesCovariables were collected using a structured questionnaire at the enrollment of the parent trial,including sociodemographic characteristics, perinatal factors, and birth outcomes.Sociodemographic characteristics included parental occupation (farmer and others), age atenrollment, and educational attainment (<3 years, primary, secondary, and high school or greater)and household wealth index. Perinatal factors—including maternal parity, self-reported age atmenarche, and BMI during the first trimester with maternal weight and height—were measured at theclinic by trained maternal and child health staff, and participants were randomly assigned to amicronutrient regimen (folic acid, iron and folic acid, or multiple micronutrients). Birth outcomesincluded SGA, which was defined as birth weight less than the 10th population percentile accordingto the INTERGROWTH-21st standard.19 The household wealth index was constructed by assessing 17different household assets or facilities (eg, bicycles, television/video compact disc devices, and




https://www.equator-network.org/reporting-guidelines/strobe/

washing machines) using the principal components method and was then categorized into tertilesindicating low, middle, and high levels of household wealth.

Statistical AnalysesData were analyzed from November 1, 2019, to May 30, 2020. Continuous variables were describedusing mean (SD) or median (interquartile range [IQR]); categorical variables, frequencies orproportions. Baseline characteristics by puberty onset were compared using χ2 tests or analysis ofvariance. Cox proportional hazard regression models were used to examine the associations of infantgrowth and rapid growth at specified periods with puberty onset with hazard ratios (HRs) and 95%CIs. Event times were defined as the age of puberty onset. The possible covariables we consideredwere parental age, parental educational level, parental occupation, household wealth index atenrollment, parity, SGA outcome at birth, maternal age at menarche, maternal BMI, and randomlyassigned regimens. Statistical significance was set at a 2-sided P < .05. All analyses were conductedwith STATA software, version 15 (StataCorp LLC).

Results

Baseline CharacteristicsTable 1 presents background characteristics by puberty onset. Among the 294 girls included in theanalysis with available data (mean [SD] age, 11.25 [0.57] years), 14 (4.8%) were born LBW; 7 (2.4%),were preterm; and 50 (17.5%) were SGA. The median age at adolescence was 11 (IQR, 11-12) years. Atotal of 241 girls (82.0%) experienced puberty onset, with a median age of 11 (IQR, 10-11) years. Inaddition, most characteristics were balanced between participants who were followed up and thosewho were lost to follow-up (eTable in the Supplement). The eFigure in the Supplement shows theflowchart of the participants.

Infant Physical Development and Adolescent Puberty OnsetTable 2 shows that adolescent girls who had higher WAZ during the first 2 years of life were morelikely to experience puberty onset. Specifically, after adjusting for covariates, a 1.00-SD increase inWAZ was associated with increased likelihood of puberty onset, with adjusted HRs of 1.15 (95% CI,0.97-1.37) at 3 months of age, 1.09 (95% CI, 0.91-1.31) at 6 months of age, 1.20 (95% CI, 1.01-1.44) at12 months of age, and 1.18 (95% CI, 0.97-1.42) at 24 months of age. However, we did not find thatLAZ or BAZ was associated with puberty onset among adolescent girls (Table 2). Null associationswere also observed for WAZ (adjusted HR, 0.92; 95% CI, 0.77-1.11) and LAZ (adjusted HR, 0.95; 95%CI, 0.84-1.06) at birth (Table 2).

In addition, we examined the associations of underweight, stunting, and overweight withadolescent puberty onset. Similarly, the results showed that adolescent girls who experiencedmalnutrition during infancy had lower likelihood of entering puberty (adjusted HR, 0.51; 95% CI,0.24-1.04), but the difference did not reach statistical significance in the multivariable analyses.

Infant Rapid Growth and Adolescent Puberty OnsetA total of 109 of 254 infants (42.9%) showed rapid weight gain from birth to 24 months of age; 133of 246 (54.1%), from birth to 3 months of age; 153 of 249 (61.4%), from birth to 6 months of age; 26of 243 (10.7%), from 6 to 12 months of age; and 19 of 251 (7.6%), from 12 to 24 months of age.However, only rapid weight gain from birth to 24 months of age and birth to 3 months of ageachieved a significant association with an increased likelihood of puberty onset among adolescentgirls, with adjusted HRs of 1.40 (95% CI, 1.01-1.93) and 1.39 (95% CI, 1.02-1.91), respectively (Table 3).

In addition, 53 of 253 infants (20.9%) showed rapid length gain from birth to 24 months of age;49 of 245 (20.0%), from birth to 3 months of age; 48 of 247 (19.4), from birth to 6 months of age;79 of 243 (32.5%), from 6 to 12 months of age; and 27 to 253 (10.7%), from 12 to 24 months of age.






Table 1. Background Characteristics of Girls by Puberty Onset in Rural Western China (N = 294)a

Characteristic All (N = 294)

Onset of puberty

Yes (n = 241) No (n = 53)Parental during pregnancy

Maternal age, mean (SD), y 23.43 (4.09) 23.51 (4.12) 23.08 (3.97)

Maternal educational attainment

<3 y 12 (4.1) 7 (58.3) 5 (41.7)

Primary 59 (20.1) 50 (84.7) 9 (15.3)

Secondary 168 (57.3) 139 (82.7) 29 (17.3)

High school or higher 54 (18.4) 45 (83.3) 9 (16.7)

Maternal occupation

Farmer 237 (80.9) 194 (81.9) 43 (18.1)

Other 56 (19.1) 46 (82.1) 10 (17.9)

Parity

0 231 (78.6) 186 (80.5) 45 (19.5)

1 49 (16.7) 43 (87.8) 6 (12.2)

≥2 14 (4.8) 12 (85.7) 2 (14.3)

Maternal age at menarche, mean (SD), y 15.23 (1.37) 15.17 (1.39) 15.46 (1.26)

Maternal BMI, mean (SD) 20.56 (2.04) 20.57 (2.04) 20.50 (2.03)

Supplement regimen

Folic acid 99 (33.7) 76 (76.8) 23 (23.2)

Iron and folic acid 94 (32.0) 78 (83.0) 16 (17.0)

Multiple micronutrients 101 (34.4) 87 (86.1) 14 (13.9)

Paternal age, mean (SD), y 26.71 (3.96) 26.73 (4.07) 26.58 (3.42)

Paternal educational attainment

<3 y 3 (1.0) 3 (100) 0

Primary 21 (7.1) 19 (90.5) 2 (9.5)

Secondary 190 (64.6) 150 (78.9) 40 (21.1)

High school or higher 80 (27.2) 69 (86.3) 11 (13.8)

Paternal occupation

Farmer 207 (70.5) 172 (83.1) 35 (16.9)

Other 87 (29.6) 69 (79.3) 18 (20.7)

Household wealth index

Low 71 (24.1) 59 (83.1) 12 (16.9)

Middle 110 (37.4) 82 (74.5) 28 (25.5)

High 113 (38.4) 100 (88.5) 13 (11.5)

Infant at birth

Birth weight, mean (SD), g 3094 (380) 3112 (368) 3013 (426)

Birth length, mean (SD), cm 48.9 (2.3) 48.9 (2.3) 48.7 (2.3)

Gestational age at delivery, mean (SD), wk 40 (1) 40 (1) 40 (2)

SGA (<10th population percentile)

No 236 (82.5) 198 (83.9) 38 (16.1)

Yes 50 (17.5) 37 (74.0) 13 (26.0)

LBW (<2500 g)

No 279 (95.2) 230 (82.4) 49 (17.6)

Yes 14 (4.8) 10 (71.4) 4 (28.6)

Preterm birth (<37 wk)

No 287 (97.6) 235 (81.9) 52 (18.1)

Yes 7 (2.4) 6 (85.7) 1 (14.3)

Infant at 12 mo

WAZ, mean (SD) 0.33 (0.87) 0.44 (0.81) −0.19 (0.95)

Underweight (WAZ < −1.00 SD)

No 245 (93.2) 207 (84.5) 38 (15.5)

Yes 18 (6.8) 9 (50.0) 9 (50.0)

LAZ, mean (SD) −0.58 (0.96) −0.48 (0.92) −1.03 (1.03)

(continued)




We did not find that rapid length gain during the aforementioned infancy periods was associated withadolescent puberty onset. Similar results were observed in unadjusted models (Table 3).

Discussion

In this prospective birth cohort study of girls conducted in rural western China, we found that themedian age of puberty onset was 11 (IQR, 10-11) years. A higher WAZ during infancy was associatedwith earlier puberty onset. Furthermore, rapid weight gain in infancy during the first 2 years of life,particularly from birth to 3 months of age, was associated with an increased likelihood of earlierpuberty onset. However, we did not find that length-related indicators during early life wereassociated with adolescent puberty onset, such as LAZ, stunting, and rapid length gain. Similar nullassociations were observed for birth weight and LAZ.

In the present study, 241 girls (82.0%) experienced puberty onset at a median age of 11 (IQR,10-11) years. Secular trend analyses showed that the median age at puberty onset in Chinese girlsdeclined from 9.8 years in 1993 to 9.2 years in 2010.25,26 However, most of the study areas werelocated in metropolises such as Shanghai and Guangzhou and did not include rural western areas,25

where malnutrition is still relatively prevalent.27 In western China, only 1 study conducted in 2001-2002 in Shaanxi Province observed puberty onset and reported a mean age of 12.1 years,28 whichwas 1 year older than our result. This discrepancy was expected given the improvement of nutritional

Table 1. Background Characteristics of Girls by Puberty Onset in Rural Western China (N = 294)a (continued)

Characteristic All (N = 294)

Onset of puberty

Yes (n = 241) No (n = 53)Stunting (LAZ < −2.00 SD)

No 247 (93.9) 208 (84.2) 39 (15.8)

Yes 16 (6.1) 8 (50.0) 8 (50.0)

BAZ, mean (SD) 0.92 (1.06) 1.00 (1.04) 0.57 (1.12)

Overweight (BAZ >2.00 SD)

No 222 (84.7) 182 (82.0) 40 (18.0)

Yes 40 (15.3) 34 (85.0) 6 (15.0)

Child at 24 mo

WAZ, mean (SD) 0.18 (0.80) 0.25 (0.78) −0.19 (0.85)

Underweight (WAZ < −1.00 SD)

No 236 (92.2) 200 (84.7) 36 (15.3)

Yes 20 (7.8) 12 (60.0) 8 (40.0)

LAZ, mean (SD) −0.89 (0.93) −0.80 (0.91) −1.33 (0.90)

Stunting (LAZ < −2.00 SD)

No 228 (88.7) 195 (85.5) 33 (14.5)

Yes 29 (11.3) 19 (65.5) 10 (34.5)

BAZ, mean (SD) 1.00 (1.00) 1.02 (0.97) 0.86 (1.13)

Overweight (BAZ >2.00 SD)

No 218 (85.5) 181 (83.0) 37 (17.0)

Yes 37 (14.5) 31 (83.8) 6 (16.2)

Early adolescence

Age, mean (SD), y 11.25 (0.57) 11.30 (0.58) 11.04 (0.48)

HAZ, mean (SD) 0.11 (1.03) 0.30 (0.97) −0.74 (0.83)

Stunting (HAZ < −2.00 SD)

No 285 (97.3) 237 (83.2) 48 (16.8)

Yes 8 (2.7) 3 (37.5) 5 (62.5)

BAZ, mean (SD) −0.39 (1.09) −0.19 (1.00) −1.29 (1.03)

Thinness (BAZ < −2.00 SD)

No 268 (92.7) 227 (84.7) 41 (15.3)

Yes 21 (7.3) 9 (42.9) 12 (57.1)

Abbreviations: BAZ, BMI-for-age z score; BMI, bodymass index (calculated as weight in kilograms dividedby square of height in meters); HAZ, height-for-age zscore; LAZ, length-for-age z score; LBW, low birthweight; SGA, small for gestational age; WAZ, weight-for-age z score.a Unless otherwise indicated, data are expressed as

No. (%) of patients. Data are missing for maternaleducational attainment (n = 1), occupation (n = 1),age at menarche (n = 6), and BMI (n = 8); at birth,infant birth weight (n = 1), birth length (n = 17), SGA(n = 8), and LBW (n = 1); at 12 months of age, WAZ(n = 31), underweight (n = 31), LAZ (n = 31), stunting(n = 31), BAZ (n = 32), and overweight (n = 32); at24 months of age, WAZ (n = 38), underweight(n = 38), LAZ (n = 37), stunting (n = 37), BAZ(n = 39), and overweight (n = 39); and in earlyadolescence, HAZ (n = 1), stunting (n = 1), BAZ(n = 5), and thinness (n = 5).




Table 2. Association of Physical Development With Puberty Onset Among Adolescent Girls in Rural Western China

Development outcome by ageParticipants with pubertyonset, No./total No. (%)a

Unadjusted Adjustedb

HR (95% CI) P value HR (95% CI) P valueWeight at critical time points during infancy and childhood

Birth

WAZ per 1.00 SD 239/291 (82.1) 1.00 (0.88-1.14) .99 0.92 (0.77-1.11) .41

Underweight (< −1.00 SD)

No 180/213 (84.5) 1 [Reference] NA 1 [Reference] NA

Yes 59/78 (75.6) 0.85 (0.63-1.14) .28 0.79 (0.50-1.26) .33

3 mo

WAZ per 1.00 SD 201/246 (81.7) 1.20 (1.03-1.39) .02 1.15 (0.97-1.37) .12



Yes 8/17 (47.1) 0.46 (0.23-0.94) .03 0.49 (0.24-1.03) .06

6 mo

WAZ per 1.00 SD 206/251 (82.1) 1.20 (1.03-1.41) .02 1.09 (0.91-1.31) .34



Yes 6/10 (60.0) 0.91 (0.40-2.04) .81 1.22 (0.50-2.94) .66

12 mo

WAZ per 1.00 SD 216/263 (82.1) 1.28 (1.10-1.49) .001 1.20 (1.01-1.44) .04



Yes 9/18 (50.0) 0.46 (0.24-0.91) .02 0.51 (0.25-1.04) .06

24 mo

WAZ per 1.00 SD 212/256 (82.8) 1.29 (1.09-1.52) .003 1.18 (0.97-1.42) .10



Yes 12/20 (60.0) 0.56 (0.31-1.01) .05 0.61 (0.33-1.15) .13

Length at critical time points during infancy and childhood

Birth

LAZ per 1.00 SD 238/289 (82.4) 0.99 (0.90 to 1.09) .88 0.95 (0.84 to 1.06) .34

Stunting (< −2.00 SD)


Yes 21/29 (72.4) 0.85 (0.54-1.33) .47 1.16 (0.83-1.62) .40

3 mo

LAZ per 1.00 SD 202/248 (81.5) 1.22 (1.05-1.41) .008 1.14 (0.97-1.35) .12



Yes 15/25 (60.0) 0.62 (0.37-1.05) .08 0.68 (0.38-1.22) .20

6 mo

LAZ per 1.00 SD 207/251 (82.5) 1.11 (0.98-1.26) .10 1.04 (0.90-1.20) .61



Yes 17/28 (60.7) 0.56 (0.34-0.92) .02 0.69 (0.41-1.17) .17

12 mo

LAZ per 1.00 SD 216/263 (82.1) 1.15 (1.00-1.31) .05 1.06 (0.90-1.24) .48



Yes 8/16 (50.0) 0.57 (0.28-1.15) .12 0.74 (0.34-1.61) .45

24 mo

LAZ per 1.00 SD 214/257 (83.3) 1.20 (1.04-1.40) .01 1.08 (0.91-1.28) .39



Yes 19/29 (65.5) 0.72 (0.45-1.16) .18 1.14 (0.67-1.95) .62

(continued)




status among children in western China during the last decade.29 However, the earlier puberty onsetobserved in developed countries warrants other explanations beyond undernutrition. Crocker et al30

reported that the secular change in age at puberty onset parallels the increasing prevalence ofoverweight and obesity in the United States. Similar changes have been observed in WesternEurope.7 Consequently, we examined the associations of infancy growth in early life with adolescentpuberty onset in an attempt to understand the mechanism behind these links.

Consistent with the Avon Longitudinal Study in British girls,31 we did not find any associationsbetween birth size and timing of puberty onset. Most studies,8,32,33 however, found that intrauterinegrowth restriction and lower birth weight were associated with earlier puberty onset. In contrast,some studies34 have reported that girls with higher birth weights tend to have earlier puberty onset.The divergent results may partly be explained by participants from different ethnicities and thedifferent analytical approaches and birth weight measures used.

To the best of our knowledge, our study is the first to fully and comparatively assess the roles ofinfant WAZ, LAZ, and BAZ during the first 2 years of puberty onset. We found that higher WAZ wasassociated with earlier puberty onset, and girls who experienced underweight in early life were lesslikely to enter puberty. In line with prior studies, which used menarche to assess puberty onset,13,14,35

we also found that infant rapid weight gain was associated with an increased likelihood of pubertyonset. Although the biological mechanisms are not yet fully illustrated, studies speculate that rapidweight gain in early life has been linked to elevated insulinlike growth factor 1 concentrations andinsulin resistance, adrenal androgen concentrations, and risk of obesity, all of which could promote

Table 2. Association of Physical Development With Puberty Onset Among Adolescent Girls in Rural Western China (continued)

Development outcome by ageParticipants with pubertyonset, No./total No. (%)a


HR (95% CI) P value HR (95% CI) P valueBMI at critical time points during infancy and childhoodc

3 mo

BAZ per 1.00 SD 201/244 (82.4) 1.08 (0.95-1.23) .26 1.07 (0.92-1.23) .40

Overweight (>2.00 SD)


Yes 43/46 (93.5) 1.14 (0.81-1.60) .44 1.03 (0.71-1.49) .87

6 mo

BAZ per 1.00 SD 206/250 (82.4) 1.08 (0.95-1.22) .26 1.04 (0.90-1.20) .57



Yes 54/62 (87.1) 1.20 (0.88-1.64) .25 1.15 (0.82-1.62) .42

12 mo

BAZ per 1.00 SD 216/262 (82.4) 1.14 (1.00-1.30) .04 1.12 (0.97-1.30) .11



Yes 34/40 (85.0) 1.19 (0.83-1.72) .35 1.18 (0.79-1.76) .41

24 mo

BAZ per 1.00 SD 212/255 (83.1) 1.10 (0.96-1.27) .18 1.09 (0.94-1.27) .25



Yes 31/37 (83.8) 1.23 (0.84-1.81) .29 1.16 (0.77-1.74) .47

Abbreviations: BAZ, BMI-for-age z score; BMI, body mass index (calculated as weight inkilograms divided by square of height in meters); HR, hazard ratio; LAZ, length-for-age zscore; NA, not applicable; WAZ, weight-for-age z score.a Denominators may differ owing to missing values.b Adjusted by small for gestational age, parental age, parental occupation, parental

educational attainment, parity, maternal age at menarche, maternal BMI, householdwealth index, and randomly assigned prenatal supplement regimens.

c The BAZ at birth is not calculated by International Fetal and Newborn GrowthConsortium for the 21st Century standards.




the activity of the gonadotropin-releasing hormone pulse generator, consequently influencing thetiming of puberty.14

In addition, our results (Table 3) show that rapid weight gain from birth to 3 months of age playsa key role in influencing the timing of puberty onset. A study from Jamaica that used different growthindicators and analytical approaches36 reported that the rapid weight gain from birth to 6 monthsof age was associated with earlier puberty onset. Similar results have been reported in other studieswith longer intervals, from birth to 12 months of age in the Danish National Birth Cohort32 and frombirth to 20 months of age in a British study.31 The lack of association in our study could be explainedby the sample size and different ethnicities. Furthermore, in these 2 studies, the information onTanner stage and weight was self-reported. Inconsistent with our null findings, a study conducted inNorth Carolina34 reported that girls with greater early weight gain from 6 to 12 months of age andfrom 12 to 24 months of age reached advanced Tanner stages at earlier ages, which may be due to thesmall sample size. Our results suggest for the first time that rapid weight gain within the first 3months of age plays an independent role in subsequent pubertal development, and postnatal growthshould be monitored closely as soon as possible after birth. In addition, some twin analyses havereported that weight gain is less likely to be influenced by genetic background during infancy thanduring childhood, suggesting a susceptible, modifiable window of infancy for long-term health

Table 3. Association Between Infant Rapid Growth and Puberty Onset

Growth metric by age

Participants withpuberty onset,No./total No. (%)a


HR (95% CI) P value HR (95% CI) P valueRapid weight gain

Birth to 3 mo


Yes 118/133 (88.7) 1.37 (1.03-1.81) .03 1.39 (1.02-1.91) .04

Birth to 6 mo


Yes 129/153 (84.3) 1.15 (0.86-1.53) .34 1.10 (0.79-1.52) .58

6 to 12 mo


Yes 22/26 (84.6) 1.08 (0.69-1.69) .73 1.01 (0.63-1.62) .98

12 to 24 mo


Yes 15/19 (78.9) 0.99 (0.58-1.67) .97 0.98 (0.55-1.75) .94

Birth to 24 mo


Yes 95/109 (87.2) 1.33 (1.02-1.75) .04 1.40 (1.01-1.93) .04

Rapid length gain

Birth to 3 mo


Yes 41/49 (83.7) 1.10 (0.78-1.55) .58 1.18 (0.81-1.73) .39

Birth to 6 mo


Yes 40/48 (83.3) 1.09 (0.77-1.54) .63 1.06 (0.72-1.55) .78

6 to 12 mo


Yes 68/79 (86.1) 1.00 (0.74-1.34) .97 1.05 (0.76-1.45) .76

12 to 24 mo


Yes 23/27 (85.2) 1.10 (0.71-1.69) .67 1.05 (0.66-1.68) .83

Birth to 24 mo


Yes 43/53 (81.1) 1.02 (0.73-1.43) .91 1.01 (0.69-1.48) .95

Abbreviations: HR, hazard ratio; NA, not applicable.a Denominators may differ owing to missing values.b Adjusted by small for gestational age, parental age,

parental occupation, parental educationalattainment, parity, maternal age at menarche,maternal BMI, household wealth index, andrandomized prenatal supplement regimens.




outcomes.37,38 Interventions designed to reduce infant rapid weight gain through early nutritionmanagement and maintain a healthy weight before, during, and after pregnancy may be feasible andpractical.39,40

We did not find that length gain was associated with puberty onset in the present study. Wehypothesize that this null finding may be due to the small number of participants who experiencedrapid length gain, ranging from 10.7% to 32.5%. However, a British cohort study reported that rapidheight changes in infancy, particularly from 4 to 12 months of age, may be related to later age atmenarche.41 The difference in findings suggests complex pathways that should be replicated in largerstudies. We could not rule out the possibility that there is no association between length gain duringinfancy and puberty onset. Woo and colleagues42 reported that faster linear growth was associatedwith higher fat-free mass and lower percentage of body fat later in life, which may support ourresults, because body fat stores but not fat-free mass influence estradiol level. Thus, although lineargrowth in early life has been shown to be associated with many subsequent health outcomes, such ascognitive and motor development,43 puberty onset may not be one of them.

To our knowledge, our study is the first to investigate the influence of infancy growth on earlypuberty onset in girls in rural western China. The Tanner stages we used to determine the onset ofpuberty are considered the standard criteria by which prepubertal and pubertal girls can be reliablydistinguished.44 This is particularly critical for girls who are in early puberty and are slightlyoverweight or obese, which may falsely suggest the presence of breast development with the stagingof thelarche by visual inspection only.

LimitationsThe study has a few limitations. First, our study was conducted within the context of a trial ofantenatal micronutrient supplementation, which may result in selection bias, limiting thegeneralizability of our results. In addition, 253 of 547 participants (46.3%) were lost to follow-up,although most of the baseline characteristics were balanced between participants who were lost tofollow-up and those who were followed up. Third, age at puberty onset for girls with Tanner stages ofgreater than 2 was self-reported, which may involve the risk of recall bias. However, given theimportance of puberty onset for girls and the short time after experiencing this milestone event, weconsidered the risk of recall bias to be acceptable. Interstaff variability in anthropometrymeasurements exists during different visits. Finally, we did not include all possible covariates, such asmaternal smoking during pregnancy, the type of feeding, excessive gestational weight gain, andstressful life events experienced during pregnancy. Future studies with strict designs are warrantedto investigate the causal association between weight gain in infancy and puberty onset.

Conclusions

In this prospective cohort study, girls who experienced rapid weight gain and had higher WAZ duringthe first 2 years of life had a higher likelihood of early onset of puberty. We identified the period ofthe first 3 months after birth as a critical window for the correlative role of weight-related indicatorsin puberty onset, indicating the necessity of monitoring weight growth as soon as possible afterbirth. Further research is needed to investigate whether these associations are causal and whetherweight growth in early life could be modified to lower subsequent disease risk.

ARTICLE INFORMATIONAccepted for Publication: March 2, 2021.

Published: May 3, 2021. doi:10.1001/jamanetworkopen.2021.6831

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





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Corresponding Authors: Zhonghai Zhu, PhD ([email protected]) and Lingxia Zeng, PhD([email protected]), Department of Epidemiology and Biostatistics, School of Public Health, Xi’an JiaotongUniversity Health Science Center, Xi’an, Shaanxi 710061, China.

Author Affiliations: Department of Epidemiology and Biostatistics, School of Public Health, Xi’an JiaotongUniversity Health Science Center, Xi’an, China (Wei, Liu, Zhu, Zeng); Department of Nutrition and Food SafetyResearch, School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, China (Cheng);Department of Obstetrics and Gynecology, Maternal and Child Health Center, The First Affiliated Hospital of HealthScience Center in Xi’an Jiaotong University, Xi’an, China (Yang); Key Laboratory of Environment and Genes Relatedto Diseases, Xi’an Jiaotong University, Ministry of Education, Xi’an, China (Zeng).

Author Contributions: Mss Wei and Liu contributed equally to this work as co–first authors. Drs Zhu and Zeng hadfull access to all the data in the study and take responsibility for the integrity of the data and the accuracy of thedata analysis.

Concept and design: Yang, Zhu, Zeng.

Acquisition, analysis, or interpretation of data: Wei, Liu, Cheng, Zhu, Zeng.

Drafting of the manuscript: Wei, Liu, Zhu.

Critical revision of the manuscript for important intellectual content: Wei, Cheng, Yang, Zhu, Zeng.

Statistical analysis: Wei, Liu, Cheng, Zhu, Zeng.

Obtained funding: Zeng.

Administrative, technical, or material support: Zhu, Zeng.

Supervision: Zhu, Zeng.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grant 81872633 from the National Natural Science Foundation ofChina (Dr Zeng) and grants 2017YFC0907200 and 2017YFC0907201 from the National Key Research andDevelopment Program of China.

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

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SUPPLEMENT.eTable. Comparison of Baseline Characteristics of the Adolescents Followed Up and Lost to Follow-upeFigure. Participant Flowchart




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association of infant physical development and rapid growth ......introduction...

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