## Abstract

As economic development increases, puberty occurs at younger ages, and this could contribute to an increase in the incidence of cardiovascular diseases and hormone-related cancers. The factors that determine pubertal timing are poorly understood. The growth axis that is active during puberty is active in the first 6 months of life and interacts with the immune system. The authors examined whether prior infections, proxied by number of hospital admissions for infections at different ages, were associated with age at pubertal onset (Tanner stage II) using interval-censored regression in the Children of 1997 cohort, which is a population-representative Chinese birth cohort (n = 7,527). Mediation by growth was also examined. Girls, but not boys, who were hospitalized for infections at least twice in the first 6 months of life experienced pubertal onset about 8 months later (mean = 10.3 years, time ratio = 1.08, 95% confidence interval: 1.04, 1.12) than did those without such hospitalizations (mean = 9.6 years) after adjustment for infant characteristics and socioeconomic position (sex interaction: P = 0.02). There were no such associations for infections at 6 months to ≤8 years of age. Growth did not mediate the association. Early infectious morbidity in girls may be associated with later puberty, perhaps via suppression of the gonadotropic axis. The lowering of the number of infections in early life that accompanies economic development could be an additional factor that contributes to earlier puberty.

Early puberty is associated with hormone-related cancers (1), cardiovascular disease (2) and its associated risk factors (3), and poor psychosocial adjustment (4). Average age at puberty has decreased sharply with economic development and is still falling in long-term developed Western countries (5, 6), developing populations (7, 8), and recently developed populations (9). Reasons for the continuing fall in age of puberty are not well understood, and they could encompass many environmental exposures, including nutrition (10, 11) and endocrine disruptors (12, 13). Another possible factor that has rarely been considered recently is exposure to or experience of infections (14). With smaller families, more vaccinations, and improved living standards, the rate of exposure to infections in infancy and childhood is declining (15). Serious infectious morbidity and mortality rates in infancy and childhood have been greatly reduced with economic development (16, 17), as has the age at pubertal onset (8, 9).

Pubertal onset is later in children with prenatally acquired human immunodeficiency virus infection (18, 19) or inflammatory bowel diseases (20). In the general population, findings on prior infections and age of puberty are limited and seemingly contradictory; more infections in infants or young children (21) but not in school-aged children are associated with later puberty (22). Experience of infections is well known to down-regulate the gonadotropic axis, either by reducing sex-steroid production or possibly through regulation of sex-steroid receptors in both humans (23–25) and animals (26–28). Infections would be expected to be associated with later puberty, perhaps with the greatest effect at times when the gonadotropic axis is active, that is, during the mini-puberty of early infancy (birth to about 6 months of age) (29, 30) or puberty (31), consistent with the observations to date (21, 22). However, it is also possible that these observations are due to infections that preclude optimal infant growth (32, 33) through growth faltering (34). To clarify this question, we took advantage of data on a large population-representative birth cohort from a developed setting, Hong Kong's Children of 1997, in which infections would be expected to have a limited influence on infant growth (35). Specifically, we tested the hypothesis that infectious morbidity in infancy, but not childhood, would be associated with later puberty without affecting growth.

## MATERIALS AND METHODS

### Data sources

The Children of 1997 birth cohort consists of 8,327 infants born in Hong Kong in April and May of 1997, comprising 88% of all births during that period. They were recruited from all 49 governmental Maternal and Child Health Centres (MCHCs), which provide free-of-charge immunizations and health and developmental surveillance (36). A self-administered survey designed to study the effects of secondhand smoke on infant health was completed by parents at the birth of the children and when those children were 3, 9, and 18 months of age (37). Passive follow-up via record linkage was instituted in 2005 to extract data on: 1) weight and height of the children from birth to 5 years of age from the MCHC records; 2) weight, height, and pubertal status from 6 to 12 years of age from the Student Health Service, Department of Health, which provides free annual check-ups for all school students (38); 3) hospital discharge records from the Hospital Authority, which manages all public hospitals (accounting for 81.4% of beds in 2005) (39); and 4) death records from the death registry. Active follow-up via direct contact was instituted in 2007. Over 89% of the original cohort had been recontacted. As of June 30, 2010, a total of 7,933 of the original 8,327 cohort members were alive, had not withdrawn from the study, and were living in Hong Kong.

### Exposures

The main exposure was number of hospital admissions (including same-day discharge and inpatient admission for at least 24 hours) for infections in public hospitals. The control exposure to examine any residual confounding by family socioeconomic position was the number of hospital admissions for accidents. Accidents, like infections, are socially patterned. With adequate control for socioeconomic position, there should be no relation between hospital episodes for accidents and age at pubertal onset. A lack of association between accidents and pubertal onset indicates less risk of residual confounding. As previously, children without any public hospital discharge records were assumed to have had no hospital admissions (40–42). The numbers of hospital admissions were considered at different ages, corresponding to different developmental stages during the first 2 main phases of growth (43), that is, mini-puberty (9 days–<6 months of age) and then 6–<24 months, 2–<5 years, and 5–8 years of age. Hospital admissions in the immediate neonatal period (≤8 days of age) were excluded. Admissions are recorded differently between the vaginally born and the surgically born with the same conditions because the vaginally born have a shorter average hospital stay for delivery than the surgically born (3.0 days vs. 7.9 days) (44). Because hospitalization data are usually not normally distributed, with a long right tail and a mode at zero (45), at each stage, the number of hospital admissions for infections was categorized as 0, 1, or ≥2 and the number for accidents was categorized as 0 or ≥1.

Consistent with our previous studies (40, 41), infections, as determined from the principal discharge code based on the International Classification of Diseases, Ninth Revision Clinical Modification (ICD-9-CM), consisted of respiratory infections (ICD–9-CM codes 33, 34.0, 381–2, 460–6, 477, 480–7, 477, and 493), gastrointestinal infections (ICD–9-CM codes 1–9, 535.0, 535.4, 535.5, 538, 558.9, and 787.91), and other infectious and parasitic diseases (ICD–9-CM codes 10–32, 34.1–139, 320–1, 370, 372.0–372.3, 390–2, 540–2, 590, 595, 599.0, 680–6, 771, 780.3, 780.6, and 787.91). Hospital admissions with ICD–9-CM codes 800–999 or E800–E999 were classified as accidents.

### Mediators

As in our previous study, infant growth was considered as change in the weight z score (standard deviation) from birth to 3 months of age and from 3 to 12 months of age (46). Childhood growth was considered as height and body mass index (BMI) z score at about 7 years (based on the closest measurement available for 6–<9 years of age) (47), corresponding to prepubertal growth, relative to the 2007 World Health Organization growth references (48).

### Outcome

The outcome was age at pubertal onset, as the earliest age when Tanner stage II for breasts (girls) or genitalia (boys) was recorded. Pubertal status was visually assessed (from age 6 years) by physicians according to the criteria of Marshall and Tanner (49, 50). Children with precocious puberty (i.e., signs of puberty before age 7.5 years in girls (n = 35) or 9 years in boys (n = 3)) were included. Children with infeasible sequences of pubertal stages, such as pubertal stage II before pubertal stage I, were excluded.

### Statistical analysis

We used multivariable interval-censored regression (51) with a lognormal distribution to examine the adjusted associations between the exposures and age at pubertal onset, from which time ratios with 95% confidence intervals are presented. A time ratio gives the comparison of ages at pubertal onset between groups, so a time ratio greater than 1 indicates older age at pubertal onset, whereas a time ratio less than 1 indicates younger age at pubertal onset. The distribution of age at pubertal onset was estimated by censoring each child in one of 3 ways: 1) left censoring if the child had experienced pubertal onset (Tanner stage II) by the first examination date; 2) interval censoring if the child had pubertal onset between 2 examination dates (i.e., the first examination date recorded Tanner stage I and the second examination date recorded Tanner stage II); and 3) right censoring if the child had not experienced pubertal onset (Tanner stage II) by the most recent examination date.

We also checked whether the associations varied by sex, from the significance of interaction terms and the heterogeneity of effects across strata. We included the interaction terms of sex with number of hospital admissions and sex with all confounders in the same model to ensure the independence of the interaction term of interest (52).

To assess whether infant or childhood growth mediated any association, we used the 4 criteria of Baron and Kenny (53), which in this case means that 1) number of hospital admissions for infections should be associated with age at pubertal onset; 2) hospital admissions for infections should be associated with infant or childhood growth, the potential mediators; 3) infant or childhood growth should be associated with age at pubertal onset; and 4) the association between hospital admissions and age at pubertal onset should be attenuated after adjustment for infant or childhood growth.

Confounders included birth weight, gestational age, birth order, breastfeeding, secondhand smoke exposure, maternal place of birth, maternal educational level, type of hospital at birth, income of household head, and Rutter score at 7 years of age, as categorized in Table 1. We used multiple imputation to predict missing confounders based on a flexible additive regression model with predictive mean matching (54), incorporating data on sex, birth weight, gestational age, birth order, method of delivery, breastfeeding, secondhand smoke exposure, parental ages, maternal place of birth, maternal educational level, maternal occupation, household income, type of hospital at birth, Rutter score at 7 years, maximum age at Tanner stage I, and minimum age at Tanner stage II (55). We summarized the results from 10 imputed data sets into single estimated time ratios with confidence intervals adjusted for missing data uncertainty (56). As a sensitivity analysis, we also performed a complete case analysis. Statistical analyses were performed using Stata, version 10 (Stata Corporation, College Station, Texas) and R, version 2.10.1 (R Development Core Team, Vienna, Austria).

Table 1.

Baseline Characteristics, by Number of Hospital Admissions, for Infections at 9 Days to 6 Months of Age in the Hong Kong Children of 1997 Birth Cohort, Hong Kong, China, 1997–2004

 Characteristic Girls (n = 3,542) Boys (n = 3,985) No. 0 (n = 3,250) 1 (n = 239) ≥2 (n = 53) No. 0 (n = 3,544) 1 (n = 336) ≥2 (n = 105) Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) % Birth weight z score 3,542 −0.2 (1.0) −0.3 (1.1) −0.3 (1.1) 3,985 −0.3 (1.0) −0.4 (1.1) −0.3 (1.0) Birth weight, kg 3,542 3,147 (419) 3,103 (484) 3,102 (462) 3,985 3,237 (448) 3,202 (501) 3,221 (452) Mean gestational age, weeks 3,542 39.0 (1.6) 38.8 (1.9) 38.8 (1.9) 3,985 38.9 (1.6) 38.8 (2.0) 38.7 (1.7) Birth order First 1,720 91.8 6.5 1.7 1,863 89.6 8.2 2.2 Second 1,436 91.5 7.4 1.1 1,695 88.8 8.6 2.6 Third or higher 386 92.5 5.4 2.1 428 86.9 8.7 4.4 Breastfeeding Never breastfed 2,011 91.1 7.3 1.5 2,279 87.6 9.4 3.1 Partially breastfed for any length of time or exclusively breastfed for <3 months 1,272 92.4 6.4 1.3 1,482 90.8 7.0 2.3 Exclusively breastfed for ≥3 months 258 93.7 3.9 2.3 224 90.6 8.8 0.6 Exposure to secondhand smoke None 993 93.9 5.0 1.0 1,072 90.1 7.2 2.7 Nonparental household smoking 1,346 91.6 7.2 1.3 1,496 90.4 7.7 1.9 Paternal smoking 1,017 91.1 7.2 1.8 1,233 86.4 10.2 3.5 Maternal smoking 187 85.1 10.6 4.3 185 87.6 10.0 2.4 Maternal place of birth Mainland China or elsewhere 1,305 90.6 7.5 2.0 1,484 85.3 10.6 4.0 Hong Kong 2,237 92.5 6.3 1.2 2,501 91.1 7.1 1.8 Maternal educational level Grade 9 or below 1,438 89.5 8.4 2.1 1,663 85.9 10.3 3.8 Grades 10–11 1,568 93.1 5.6 1.3 1,725 90.7 7.2 2.1 Grade 12 or above 536 93.8 5.6 0.6 597 92.1 6.9 1.0 Type of hospital at birth Private 2,565 90.2 7.8 2.0 2,858 86.4 10.2 3.5 Public 977 95.8 3.9 0.3 1,127 95.5 4.0 0.6 Annual income of household head, dollarsa Quintile 1: mean = 1,741 (SD, 408) 709 90.3 7.2 2.5 808 84.7 10.2 5.0 Quintile 2: mean = 2,846 (SD, 328) 745 87.4 10.1 2.5 833 86.5 10.2 3.4 Quintile 3: mean = 4,362 (SD, 556) 688 92.6 6.0 1.4 815 86.9 10.4 2.7 Quintile 4: mean = 6,805 (SD, 874) 697 94.2 5.0 0.7 760 92.6 6.3 1.1 Quintile 5: mean = 14,678 (SD, 15,497) 703 94.5 5.1 0.3 770 94.5 4.7 0.8 Weight z score change at 0–3 months of age 3,542 0.3 (0.9) 0.3 (0.9) 0.0 (1.1) 3,985 0.3 (0.9) 0.3 (0.9) 0.3 (1.1) Weight z score change at 3–12 months of age 3,542 0.0 (0.6) 0.1 (0.7) 0.2 (0.8) 3,985 −0.1 (0.7) 0.0 (0.7) 0.0 (0.7) Body mass indexbz score at 7 years of age 3,542 0.0 (1.0) 0.1 (1.1) −0.2 (1.0) 3,985 0.3 (1.3) 0.4 (1.4) 0.3 (1.3) Height z score at 7 years of age 3,542 −0.1 (0.9) −0.1 (1.0) −0.4 (0.8) 3,985 −0.1 (0.9) −0.1 (1.0) 0.1 (0.9) Rutter score at 7 years of age <13 points 2,793 92.0 6.6 1.4 2,739 89.1 8.2 2.7 >13 points 749 91.0 7.3 1.7 1,246 88.5 8.9 2.6
 Characteristic Girls (n = 3,542) Boys (n = 3,985) No. 0 (n = 3,250) 1 (n = 239) ≥2 (n = 53) No. 0 (n = 3,544) 1 (n = 336) ≥2 (n = 105) Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) % Birth weight z score 3,542 −0.2 (1.0) −0.3 (1.1) −0.3 (1.1) 3,985 −0.3 (1.0) −0.4 (1.1) −0.3 (1.0) Birth weight, kg 3,542 3,147 (419) 3,103 (484) 3,102 (462) 3,985 3,237 (448) 3,202 (501) 3,221 (452) Mean gestational age, weeks 3,542 39.0 (1.6) 38.8 (1.9) 38.8 (1.9) 3,985 38.9 (1.6) 38.8 (2.0) 38.7 (1.7) Birth order First 1,720 91.8 6.5 1.7 1,863 89.6 8.2 2.2 Second 1,436 91.5 7.4 1.1 1,695 88.8 8.6 2.6 Third or higher 386 92.5 5.4 2.1 428 86.9 8.7 4.4 Breastfeeding Never breastfed 2,011 91.1 7.3 1.5 2,279 87.6 9.4 3.1 Partially breastfed for any length of time or exclusively breastfed for <3 months 1,272 92.4 6.4 1.3 1,482 90.8 7.0 2.3 Exclusively breastfed for ≥3 months 258 93.7 3.9 2.3 224 90.6 8.8 0.6 Exposure to secondhand smoke None 993 93.9 5.0 1.0 1,072 90.1 7.2 2.7 Nonparental household smoking 1,346 91.6 7.2 1.3 1,496 90.4 7.7 1.9 Paternal smoking 1,017 91.1 7.2 1.8 1,233 86.4 10.2 3.5 Maternal smoking 187 85.1 10.6 4.3 185 87.6 10.0 2.4 Maternal place of birth Mainland China or elsewhere 1,305 90.6 7.5 2.0 1,484 85.3 10.6 4.0 Hong Kong 2,237 92.5 6.3 1.2 2,501 91.1 7.1 1.8 Maternal educational level Grade 9 or below 1,438 89.5 8.4 2.1 1,663 85.9 10.3 3.8 Grades 10–11 1,568 93.1 5.6 1.3 1,725 90.7 7.2 2.1 Grade 12 or above 536 93.8 5.6 0.6 597 92.1 6.9 1.0 Type of hospital at birth Private 2,565 90.2 7.8 2.0 2,858 86.4 10.2 3.5 Public 977 95.8 3.9 0.3 1,127 95.5 4.0 0.6 Annual income of household head, dollarsa Quintile 1: mean = 1,741 (SD, 408) 709 90.3 7.2 2.5 808 84.7 10.2 5.0 Quintile 2: mean = 2,846 (SD, 328) 745 87.4 10.1 2.5 833 86.5 10.2 3.4 Quintile 3: mean = 4,362 (SD, 556) 688 92.6 6.0 1.4 815 86.9 10.4 2.7 Quintile 4: mean = 6,805 (SD, 874) 697 94.2 5.0 0.7 760 92.6 6.3 1.1 Quintile 5: mean = 14,678 (SD, 15,497) 703 94.5 5.1 0.3 770 94.5 4.7 0.8 Weight z score change at 0–3 months of age 3,542 0.3 (0.9) 0.3 (0.9) 0.0 (1.1) 3,985 0.3 (0.9) 0.3 (0.9) 0.3 (1.1) Weight z score change at 3–12 months of age 3,542 0.0 (0.6) 0.1 (0.7) 0.2 (0.8) 3,985 −0.1 (0.7) 0.0 (0.7) 0.0 (0.7) Body mass indexbz score at 7 years of age 3,542 0.0 (1.0) 0.1 (1.1) −0.2 (1.0) 3,985 0.3 (1.3) 0.4 (1.4) 0.3 (1.3) Height z score at 7 years of age 3,542 −0.1 (0.9) −0.1 (1.0) −0.4 (0.8) 3,985 −0.1 (0.9) −0.1 (1.0) 0.1 (0.9) Rutter score at 7 years of age <13 points 2,793 92.0 6.6 1.4 2,739 89.1 8.2 2.7 >13 points 749 91.0 7.3 1.7 1,246 88.5 8.9 2.6

Abbreviation: SD, standard deviation.

a

US $1 = HK$7.80.

b

Weight (kg)/height (m)2.

### Ethics approval

We obtained ethical approval from the University of Hong Kong-Hospital Authority Hong Kong West Cluster Joint Institutional Review Board and the Ethics Committee of the Department of Health, Government of the Hong Kong Special Administrative Region.

## RESULTS

Of the 7,527 children (90% follow-up rate) for whom we had information about age at pubertal onset, 76% of the girls (2,695) and 42% of the boys (1,671) had experienced pubertal onset. Income was imputed for 10.3% of the children, maternal place of birth for 8.4%, secondhand smoke or breastfeeding for 2.4%, and maternal educational level or type of hospital at birth for 1.1%. The estimated mean age at pubertal onset was 11.7 years in boys (95% confidence interval: 11.6, 11.8) and 9.6 years in girls (95% confidence interval: 9.5, 9.6)—numbers that were very similar to what was previously observed in Hong Kong (9). In the first 6 months of life, 8% had 1 hospitalization for infections and 2% had ≥2; more boys (2.6%) than girls (1.5%) had at least 2 hospitalizations for infections. In the same period, 0.5% had hospitalizations for accidents.

Table 1 shows that children with ≥2 hospitalizations for infections in the first 6 months of life were more likely to never have been breastfed and to have been exposed to paternal or maternal smoking. They also had lower family socioeconomic positions and mothers from mainland China or elsewhere. Children hospitalized for infections in later infancy and childhood (6 months to 8 years of age) were also likely to be from families of lower socioeconomic position (Web Tables 1 and 2, available at http://aje.oxfordjournals.org/). Girls, but not boys, hospitalized for infections in early infancy tended to grow slowly at 0–3 months of age and show positive weight change at 3–12 months of age, but they were not thinner or shorter at 7 years of age. Higher BMI and height at 7 years of age were associated with younger age at pubertal onset in both sexes (Table 2). Weight gain at 0–3 months and at 3–12 months was associated with younger age at pubertal onset in boys but not in girls.

Table 2.

Unadjusted Associations Between Baseline Characteristics and Age at Pubertal Onset in the Hong Kong Children of 1997 Birth Cohort, Hong Kong, China, 1997–2004

 Characteristic Girls (n = 3,542) Boys (n = 3,985) No. Time Ratio 95% CI No. Time Ratio 95% CI Birth weight z score 3,542 1.00 0.99, 1.00 3,985 1.00 0.99, 1.00 Gestational age 3,542 0.99 0.99, 1.00 3,985 1.00 1.00, 1.00 Birth order First 1,720 Reference 1,863 Reference Second 1,436 1.00 0.99, 1.01 1,695 1.00 0.99, 1.01 Third or higher 386 1.00 0.98, 1.02 428 1.00 0.98, 1.01 Breastfeeding Never breastfed 2,011 Reference 2,279 Reference Partially breastfed for any length of time or exclusively breastfed for <3 months 1,272 1.01 1.00, 1.02 1,482 1.00 0.99, 1.01 Exclusively breastfed for ≥3 months 258 0.99 0.97, 1.01 224 1.00 0.98, 1.02 Exposure to secondhand smoke None 993 Reference 1,072 Reference Nonparental household smoking 1,346 1.01 1.00, 1.02 1,496 1.00 0.99, 1.01 Paternal smoking 1,017 1.00 0.99, 1.02 1,233 1.00 0.99, 1.01 Maternal smoking 187 1.01 0.98, 1.03 185 1.02 1.00, 1.04 Maternal place of birth Mainland China or elsewhere 1,305 Reference 1,484 Reference Hong Kong 2,237 1.02 1.01, 1.03 2,501 1.01 1.00, 1.02 Maternal educational level Grade 9 or below 1,438 Reference 1,663 Reference Grades 10–11 1,568 1.02 1.00, 1.03 1,725 1.00 0.99, 1.01 Grade 12 or above 536 1.02 1.00, 1.03 597 0.99 0.98, 1.00 Type of hospital at birth Private 2,565 Reference 2,858 Reference Public 977 1.01 1.00, 1.02 1,127 1.00 0.99, 1.01 Annual income of household head, dollars Quintile 1: mean = 1,741 (SD, 408) 709 Reference 808 Reference Quintile 2: mean = 2,846 (SD, 328) 745 1.00 0.98, 1.01 833 0.99 0.98, 1.01 Quintile 3: mean = 4,362 (SD, 556) 688 1.00 0.99, 1.02 815 0.99 0.98, 1.00 Quintile 4: mean = 6,805 (SD, 874) 697 1.01 0.99, 1.03 760 1.00 0.98, 1.01 Quintile 5: mean = 14,678 (SD, 15,497) 703 1.03 1.01, 1.04 770 0.99 0.98, 1.01 Weight z score change at 0–3 months 3,542 1.00 0.99, 1.00 3,985 1.00 0.99, 1.00 Weight z score change at 3–12 months 3,542 0.99 0.98, 1.00 3,985 0.99 0.99, 1.00 Body mass indexaz score at 7 years of age 3,542 0.97 0.97, 0.98 3,985 0.99 0.99, 1.00 Height z score at 7 years of age 3,542 0.96 0.95, 0.96 3,985 0.98 0.97, 0.98 Rutter score at 7 years of age <13 points 2,793 Reference 2,739 Reference ≥13 points 749 1.01 1.00, 1.02 1,246 1.00 0.99, 1.01
 Characteristic Girls (n = 3,542) Boys (n = 3,985) No. Time Ratio 95% CI No. Time Ratio 95% CI Birth weight z score 3,542 1.00 0.99, 1.00 3,985 1.00 0.99, 1.00 Gestational age 3,542 0.99 0.99, 1.00 3,985 1.00 1.00, 1.00 Birth order First 1,720 Reference 1,863 Reference Second 1,436 1.00 0.99, 1.01 1,695 1.00 0.99, 1.01 Third or higher 386 1.00 0.98, 1.02 428 1.00 0.98, 1.01 Breastfeeding Never breastfed 2,011 Reference 2,279 Reference Partially breastfed for any length of time or exclusively breastfed for <3 months 1,272 1.01 1.00, 1.02 1,482 1.00 0.99, 1.01 Exclusively breastfed for ≥3 months 258 0.99 0.97, 1.01 224 1.00 0.98, 1.02 Exposure to secondhand smoke None 993 Reference 1,072 Reference Nonparental household smoking 1,346 1.01 1.00, 1.02 1,496 1.00 0.99, 1.01 Paternal smoking 1,017 1.00 0.99, 1.02 1,233 1.00 0.99, 1.01 Maternal smoking 187 1.01 0.98, 1.03 185 1.02 1.00, 1.04 Maternal place of birth Mainland China or elsewhere 1,305 Reference 1,484 Reference Hong Kong 2,237 1.02 1.01, 1.03 2,501 1.01 1.00, 1.02 Maternal educational level Grade 9 or below 1,438 Reference 1,663 Reference Grades 10–11 1,568 1.02 1.00, 1.03 1,725 1.00 0.99, 1.01 Grade 12 or above 536 1.02 1.00, 1.03 597 0.99 0.98, 1.00 Type of hospital at birth Private 2,565 Reference 2,858 Reference Public 977 1.01 1.00, 1.02 1,127 1.00 0.99, 1.01 Annual income of household head, dollars Quintile 1: mean = 1,741 (SD, 408) 709 Reference 808 Reference Quintile 2: mean = 2,846 (SD, 328) 745 1.00 0.98, 1.01 833 0.99 0.98, 1.01 Quintile 3: mean = 4,362 (SD, 556) 688 1.00 0.99, 1.02 815 0.99 0.98, 1.00 Quintile 4: mean = 6,805 (SD, 874) 697 1.01 0.99, 1.03 760 1.00 0.98, 1.01 Quintile 5: mean = 14,678 (SD, 15,497) 703 1.03 1.01, 1.04 770 0.99 0.98, 1.01 Weight z score change at 0–3 months 3,542 1.00 0.99, 1.00 3,985 1.00 0.99, 1.00 Weight z score change at 3–12 months 3,542 0.99 0.98, 1.00 3,985 0.99 0.99, 1.00 Body mass indexaz score at 7 years of age 3,542 0.97 0.97, 0.98 3,985 0.99 0.99, 1.00 Height z score at 7 years of age 3,542 0.96 0.95, 0.96 3,985 0.98 0.97, 0.98 Rutter score at 7 years of age <13 points 2,793 Reference 2,739 Reference ≥13 points 749 1.01 1.00, 1.02 1,246 1.00 0.99, 1.01

Abbreviations: CI, confidence interval; SD, standard deviation.

a

Weight (kg)/height (m)2.

The associations between hospital admissions for infections and age at pubertal onset differed by sex in the first 6 months of life (P for interaction = 0.02) but not later (P value for interaction: at 6–<24 months of age P = 0.81, at 2–<5 years, P = 0.08, and at 5–8 years, P = 0.76). Table 3 shows that girls, but not boys, who had at least 2 hospitalizations for infections in the first 6 months of life had older age at pubertal onset than did those with no hospital admissions after adjustment for birth weight, gestational age, birth order, breastfeeding, secondhand smoke, maternal place of birth, maternal educational level, type of hospital at birth, household income per head, and Rutter score at 7 years. The number of hospital admissions for infections in later infancy or early childhood (6 months to 8 years of age) was not associated with age at pubertal onset in boys or girls. There was no association between number of hospital admissions for accidents and age at pubertal onset. The complete-case analysis produced similar results (Appendix Table 1).

Table 3.

Adjusteda Associations Between Number of Hospital Admissions for Infections and Accidents at Different Stages and Age at Pubertal Onset in the Hong Kong Children of 1997 Birth Cohort, Hong Kong, China, 1997–2004

 No. of Hospital Admissions by Age Group and Cause Girls (n = 3,542) Boys (n = 3,985) No. Time Ratio 95% CI No. Time Ratio 95% CI 9 days–<6 months Infections 0 3,250 Reference 3,544 Reference 1 239 1.00 0.99, 1.02 336 1.01 0.99, 1.02 ≥2 53 1.08 1.04, 1.12 105 1.01 0.98, 1.03 Accidents 0 3,522 Reference 3,966 Reference ≥1 20 0.97 0.91, 1.03 19 1.02 0.96, 1.08 6–<24 months Infections 0 2,959 Reference 3,096 Reference 1 440 1.01 0.99, 1.02 619 1.00 0.99, 1.01 ≥2 143 1.00 0.97, 1.02 270 1.00 0.98, 1.02 Accidents 0 3,468 Reference 3,893 Reference ≥1 74 1.00 0.97, 1.03 92 0.97 0.94, 1.00 2–<5 years Infections 0 3,002 Reference 3,255 Reference 1 430 1.01 1.00, 1.03 526 0.99 0.98, 1.01 ≥2 110 0.99 0.96, 1.01 204 1.01 0.99, 1.03 Accidents 0 3,443 Reference 3,864 Reference ≥1 99 1.03 1.00, 1.06 121 0.99 0.96, 1.01 5–8 years Infections 0 3,369 Reference 3,759 Reference 1 155 1.00 0.98, 1.03 195 0.99 0.97, 1.01 ≥2 18 1.01 0.95, 1.07 31 1.00 0.95, 1.06 Accidents 0 3,480 Reference 3,888 Reference ≥1 62 1.01 0.97, 1.04 97 1.00 0.97, 1.03
 No. of Hospital Admissions by Age Group and Cause Girls (n = 3,542) Boys (n = 3,985) No. Time Ratio 95% CI No. Time Ratio 95% CI 9 days–<6 months Infections 0 3,250 Reference 3,544 Reference 1 239 1.00 0.99, 1.02 336 1.01 0.99, 1.02 ≥2 53 1.08 1.04, 1.12 105 1.01 0.98, 1.03 Accidents 0 3,522 Reference 3,966 Reference ≥1 20 0.97 0.91, 1.03 19 1.02 0.96, 1.08 6–<24 months Infections 0 2,959 Reference 3,096 Reference 1 440 1.01 0.99, 1.02 619 1.00 0.99, 1.01 ≥2 143 1.00 0.97, 1.02 270 1.00 0.98, 1.02 Accidents 0 3,468 Reference 3,893 Reference ≥1 74 1.00 0.97, 1.03 92 0.97 0.94, 1.00 2–<5 years Infections 0 3,002 Reference 3,255 Reference 1 430 1.01 1.00, 1.03 526 0.99 0.98, 1.01 ≥2 110 0.99 0.96, 1.01 204 1.01 0.99, 1.03 Accidents 0 3,443 Reference 3,864 Reference ≥1 99 1.03 1.00, 1.06 121 0.99 0.96, 1.01 5–8 years Infections 0 3,369 Reference 3,759 Reference 1 155 1.00 0.98, 1.03 195 0.99 0.97, 1.01 ≥2 18 1.01 0.95, 1.07 31 1.00 0.95, 1.06 Accidents 0 3,480 Reference 3,888 Reference ≥1 62 1.01 0.97, 1.04 97 1.00 0.97, 1.03

Abbreviation: CI, confidence interval.

a

Adjusted for birth weight, gestational age, birth order, breastfeeding, secondhand smoke, maternal place of birth, maternal educational level, type of hospital at birth, income of household head, and Rutter score at 7 years of age.

Both infant and childhood growth only partially fulfilled the mediation criteria, because infant growth was not associated with age at pubertal onset in girls or with number of hospital admissions for infections in boys. Also, the number of hospital admissions for infections in the first 6 months of life was not associated with childhood growth in girls or boys. Moreover, the associations between hospital admissions for infections in the first 6 months of life and age at pubertal onset remained unchanged after additionally adjustment for infant and childhood growth separately or simultaneously (Table 4).

Table 4.

Associations Between Number of Hospital Admissions for Infections at 9 Days to 6 Months and Age at Pubertal Onset With Adjustment for Different Combinations of Growth Markersa, Hong Kong, China, 1997–2004

 Model and No. of Hospital Admissions Girls (n = 3,542) Boys (n = 3,985) Time Ratio 95% CI Time Ratio 95% CI Model 1: unadjusted 0 Reference Reference 1 1.00 0.98, 1.02 1.00 0.99, 1.02 ≥2 1.07 1.03, 1.12 1.00 0.98, 1.03 Model 2: adjusted for weight z score change at 0–3 months of age 0 Reference Reference 1 1.00 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.07 1.03, 1.12 1.01 0.98, 1.03 Model 3: adjusted for weight z score change at 3–12 months of age 0 Reference Reference 1 1.01 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.08 1.04, 1.13 1.01 0.98, 1.04 Model 4: adjusted for weight z score change at 0–3 months and 3–12 months of age 0 Reference Reference 1 1.00 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.08 1.03, 1.12 1.01 0.98, 1.04 Model 5: adjusted for BMIbz score at 7 years of age 0 Reference Reference 1 1.01 0.99, 1.03 1.01 0.99, 1.02 ≥2 1.07 1.03, 1.11 1.01 0.98, 1.03 Model 6: adjusted for height z score at 7 years of age 0 Reference Reference 1 1.01 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.06 1.02, 1.10 1.01 0.98, 1.04 Model 7: adjusted for height and BMI z scores at 7 years of age 0 Reference Reference 1 1.01 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.06 1.02, 1.10 1.01 0.98, 1.04 Model 8: adjusted for weight z score change at 0–3 months and 3–12 months of age and height and BMI z scores at 7 years of age 0 Reference Reference 1 1.01 0.99, 1.03 1.01 0.99, 1.02 ≥2 1.06 1.03, 1.11 1.01 0.98, 1.04
 Model and No. of Hospital Admissions Girls (n = 3,542) Boys (n = 3,985) Time Ratio 95% CI Time Ratio 95% CI Model 1: unadjusted 0 Reference Reference 1 1.00 0.98, 1.02 1.00 0.99, 1.02 ≥2 1.07 1.03, 1.12 1.00 0.98, 1.03 Model 2: adjusted for weight z score change at 0–3 months of age 0 Reference Reference 1 1.00 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.07 1.03, 1.12 1.01 0.98, 1.03 Model 3: adjusted for weight z score change at 3–12 months of age 0 Reference Reference 1 1.01 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.08 1.04, 1.13 1.01 0.98, 1.04 Model 4: adjusted for weight z score change at 0–3 months and 3–12 months of age 0 Reference Reference 1 1.00 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.08 1.03, 1.12 1.01 0.98, 1.04 Model 5: adjusted for BMIbz score at 7 years of age 0 Reference Reference 1 1.01 0.99, 1.03 1.01 0.99, 1.02 ≥2 1.07 1.03, 1.11 1.01 0.98, 1.03 Model 6: adjusted for height z score at 7 years of age 0 Reference Reference 1 1.01 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.06 1.02, 1.10 1.01 0.98, 1.04 Model 7: adjusted for height and BMI z scores at 7 years of age 0 Reference Reference 1 1.01 0.99, 1.02 1.01 0.99, 1.02 ≥2 1.06 1.02, 1.10 1.01 0.98, 1.04 Model 8: adjusted for weight z score change at 0–3 months and 3–12 months of age and height and BMI z scores at 7 years of age 0 Reference Reference 1 1.01 0.99, 1.03 1.01 0.99, 1.02 ≥2 1.06 1.03, 1.11 1.01 0.98, 1.04

Abbreviations: BMI, body mass index; CI, confidence interval.

a

Models 2–8 were adjusted for birth weight, gestational age, birth order, breastfeeding, secondhand smoke, maternal place of birth, maternal educational level, type of hospital at birth, income of household head, and Rutter score at 7 years of age.

b

Weight (kg)/height (m)2.

## DISCUSSION

In the present cohort, a contemporary, population-representative Hong Kong Chinese birth cohort with a high follow-up rate, girls hospitalized for infections in early infancy (<6 months of age) but not in later infancy or early childhood (6 months to 8 years of age) had older age at pubertal onset, consistent with a previously reported positive association of infections in infancy (3 months to 3 years of age) with late age of menarche (21) but not of childhood (birth to 8 years of age) infections (22). In boys, the number of hospital admissions for infections in the first 8 years of life was unrelated to age at pubertal onset. To our knowledge, this is the first study that clearly distinguishes the effect of infections in infancy from that of infections in childhood. In addition, our cohort was large enough to allow us to distinguish between the sexes. We found that the association was specific to girls, which is consistent with relatively later pubertal onset in girls than in boys with prenatally acquired human immunodeficiency virus infections (19). Additionally, we found no evidence of mediation by infant or childhood growth. There was also no association between hospital admissions for accidents and age at pubertal onset, which suggested minimal confounding by family socioeconomic position. Our study adds to the literature by showing that, consistent with our hypothesis, infections in early infancy but not later infancy or childhood were associated with later puberty in girls, independent of growth.

This large birth cohort, with its strength of case ascertainment based on public hospital discharge records, clinically assessed pubertal onset, and routinely measured anthropometric data, nevertheless has several limitations. First, we only assessed the effects of serious infectious morbidity that warranted hospitalizations, because these were more likely to have a long-term impact. Second, we cannot rule out the possibility of selection bias, given that undergoing check-ups provided by the Student Health Service is voluntary. However, there was a high follow-up rate (90% of the eligible cohort members), and children with follow-up were similar to those without it. Cohen effect sizes for sex (0.05), number of hospital admissions at different stages (<0.15), and family socioeconomic position (<0.21) were relatively small. Our results could have been biased if we had systematically excluded those children with serious infections in early infancy and pubertal onset at younger ages, though we could not see how that would be. Third, we acknowledge that collating a complete medical history for each child would provide a more comprehensive review of a child's history of infections. However, this is not possible in Hong Kong, where most primary care is privately provided. Although most hospital use is in the public sector, there is some limited private hospital use. However, parents who brought their infants to MCHCs and Student Health Service Centres were most likely to bring their children to public rather than private hospitals, as MCHCs and Student Health Service Centres were free and public hospitals were almost free. Moreover, we used accidents as a counterexample to give an indication of the level of residual confounding. Fourth, breast development misclassification by visual assessment is more likely in overweight girls (57). In our study, the prevalence of International Obesity Task Force-defined overweight (including obesity) at 7 years was 11.5% in girls; however, there was no association between childhood overweight and number of hospital admissions for infections (data not shown). Fifth, pubertal development was assessed by different physicians at 12 Student Health Service Centres. A standard guideline for staging and an orchiometer is available. Any random variation in pubertal assessment would reduce the precision of estimates. Finally, there may be differences in the use of hospitals by cause (e.g., accidents compared with infections), which would reduce the validity of using accidents as a control exposure.

There are several possible explanations for our observed association between specifically early life infections (in the first 6 months) and pubertal onset at an older age in girls. First, infant girls who were hospitalized before 6 months of age were smaller at birth, which could be associated with puberty at younger ages (58). However, we found an association between older age at pubertal onset adjusted for birth weight and gestational age. Second, infants hospitalized for infections might have congenital abnormalities that make them more vulnerable to infections. However, if congenital illness were the underlying cause, we would have expected the same association in boys. Third, several maternal characteristics potentially affect age of puberty, such as maternal age at menarche, prepregnancy BMI, and smoking during pregnancy (59). However, maternal adiposity and smoking, which tend to be positively associated with infant infections (60, 61) and negatively associated with the timing of puberty (59), are relatively uncommon in our population (62, 63) and thus may be less influential confounders. Further, although maternal age at menarche is a strong predictor of age of puberty (64), we have no reason to think that a mother's later menarche would increase specifically her infant daughter's susceptibility to infections. Moreover, sex-specific findings are unlikely to be due to residual or uncontrolled socioeconomic confounding. Finally, in this currently ongoing birth cohort, nearly half (42%) of the boys had pubertal onset compared with 76% of girls. We cannot rule out the possibility that the lack of association in boys could be because late-maturing boys are more susceptible to the effects of infections. However, 42% of boys had reached Tanner stage II.

Our findings may reflect the physiologic effects of infections during early infancy. One possible mechanism is growth faltering. Rapid infant weight gain is associated with earlier puberty (65). Infants with serious infectious morbidity may grow more slowly (34). However, we found that serious infections had little effect on infant growth in boys. Although girls with early infections grew slowly at 0–3 months and then faster at 3–12 months of age, we did not find any mediation by infant growth. Nonetheless, infectious morbidity may induce changes in body composition. Childhood overweight is associated with earlier puberty (66). Attaining a certain level of body weight or specifically body fat has been postulated as triggering pubertal onset (67, 68). Higher BMI at 7 years of age was associated with younger age at pubertal onset in our cohort, but there was no association between infections in early life and BMI at 7 years of age and also no mediation by childhood BMI. As such, our finding of an association between infections and puberty independent of infant or childhood growth suggests that the effect of infections is unlikely to operate via the somatotropic axis.

Alternatively, infections may suppress the gonadotropic axis. There are marked physiologic rises in levels of testosterone in boys and estrogen in girls together with marked genitalia development during the first 6 months of life (29, 30, 69), which indicates potential plasticity in early infancy. Our findings coincide with the physiologic pattern of gonadotropic axis activation; that is, associations with infections were only observed when the axis is active (“mini-puberty”), not when it is quiescent (“juvenile state”), suggesting infancy as a potentially critical period of exposure regulating pubertal onset. Experience of infections reduces sex steroid levels in animals (26) and humans (23–25), although the biologic mechanism by which the immune system in infancy permanently affects the gonadotropic axis in boys and girls remains to be elucidated. Women and men may have different life history strategies for maximizing their descendants. Women may gain more than men by playing a grandparent role (70, 71), which would make investing in the immune system at the expense of reproduction a better life history strategy for women than for men (72).

From a public health perspective, there are several implications of our findings. First, the reduced experience of and exposure to infections in early life that come with economic development may be additional factors that contribute to earlier pubertal onset in girls. Second, although secular trends of earlier puberty and taller height usually occur with improved living conditions (6, 73), they do not usually coincide (74, 75), and the biologic mechanisms that control pubertal onset may not be the same as those that control linear growth. This may explain why adopted girls have earlier puberty than do their counterparts in the country of origin but similar final heights (76, 77). Finally, the improved living conditions that accompany economic development, including more food and fewer infections, may produce higher pubertal sex steroid levels over generations (78), with corresponding implications for any related diseases, such as hormone-related cancers, suggesting that reduced exposure to infections may be one of the potential drivers of changes in patterns of adult disease with economic development.

### Abbreviations

Abbreviations
• BMI

body mass index

• ICD-9-CM

International Classification of Diseases, Ninth Revision, Clinical Modification

• MCHCs

Maternal and Child Health Centres

Author affiliations: Life Course and Lifestyle Epidemiology Group, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China (Man Ki Kwok, Gabriel M. Leung, Tai Hing Lam, C. Mary Schooling).

This work was a substudy of the Children of 1997 birth cohort, which was initially supported by the Health Care and Promotion Fund, Health and Welfare Bureau, Government of the Special Administrative Region, China (grant 216106). Since 2005, the birth cohort study has been funded by the Health and Health Services Research Fund (grant 03040771) and the Research Fund for the Control of Infectious Diseases in Hong Kong (grants 04050172 and 06060592), Government of the Hong Kong Special Administrative Region, and the University Research Committee Strategic Research Theme of Public Health, University of Hong Kong.

The authors thank colleagues at the Student Health Service and Family Health Service of the Department of Health for their assistance and collaboration. They also thank Dr. Connie Hui for her assistance with the record linkage and the late Dr. Connie O for coordinating the project and all of the fieldwork for the initial study in 1997–1998.

Conflict of interest: none declared.

### APPENDIX

Appendix Table 1.

Complete-Case Analysis for Adjusteda Associations Between Number of Hospital Admissions for Infections and Accidents at Different Stages and Age at Pubertal Onset in the Hong Kong Children of 1997 Birth Cohort, Hong Kong, China, 1997–2004

 No. of Hospital Admissions by Age Group and Cause Girls (n = 3,030) Boys (n = 3,363) No. Time Ratio 95% CI No. Time Ratio 95% CI 9 days–<6 months Infections 0 2,779 Reference 3,000 Reference 1 203 1.01 0.99, 1.03 277 1.01 0.99, 1.02 ≥2 48 1.07 1.03, 1.12 86 1.00 0.97, 1.04 Accidents 0 3,011 Reference 3,348 Reference ≥1 19 0.98 0.92, 1.04 15 1.04 0.97, 1.12 6–<24 months Infections 0 2,528 Reference 2,608 Reference 1 375 1.00 0.99, 1.02 523 1.00 0.99, 1.01 ≥2 127 0.99 0.97, 1.02 232 1.00 0.98, 1.02 Accidents 0 2,973 Reference 3,290 Reference ≥1 57 0.99 0.96, 1.03 73 0.97 0.94, 1.00 2–<5 years Infections 0 2,565 Reference 2,744 Reference 1 370 1.01 1.00, 1.03 452 1.00 0.98, 1.01 ≥2 95 0.99 0.96, 1.02 167 1.01 0.98, 1.03 Accidents 0 2,951 Reference 3,268 Reference ≥1 79 1.03 1.00, 1.07 95 0.99 0.97, 1.02 5–8 years Infections 0 2,888 Reference 3,179 Reference 1 126 1.00 0.97, 1.03 161 0.99 0.97, 1.01 ≥2 16 1.00 0.94, 1.07 23 1.00 0.95, 1.06 Accidents 0 2,980 Reference 3,285 Reference ≥1 50 1.01 0.97, 1.05 78 1.01 0.98, 1.04
 No. of Hospital Admissions by Age Group and Cause Girls (n = 3,030) Boys (n = 3,363) No. Time Ratio 95% CI No. Time Ratio 95% CI 9 days–<6 months Infections 0 2,779 Reference 3,000 Reference 1 203 1.01 0.99, 1.03 277 1.01 0.99, 1.02 ≥2 48 1.07 1.03, 1.12 86 1.00 0.97, 1.04 Accidents 0 3,011 Reference 3,348 Reference ≥1 19 0.98 0.92, 1.04 15 1.04 0.97, 1.12 6–<24 months Infections 0 2,528 Reference 2,608 Reference 1 375 1.00 0.99, 1.02 523 1.00 0.99, 1.01 ≥2 127 0.99 0.97, 1.02 232 1.00 0.98, 1.02 Accidents 0 2,973 Reference 3,290 Reference ≥1 57 0.99 0.96, 1.03 73 0.97 0.94, 1.00 2–<5 years Infections 0 2,565 Reference 2,744 Reference 1 370 1.01 1.00, 1.03 452 1.00 0.98, 1.01 ≥2 95 0.99 0.96, 1.02 167 1.01 0.98, 1.03 Accidents 0 2,951 Reference 3,268 Reference ≥1 79 1.03 1.00, 1.07 95 0.99 0.97, 1.02 5–8 years Infections 0 2,888 Reference 3,179 Reference 1 126 1.00 0.97, 1.03 161 0.99 0.97, 1.01 ≥2 16 1.00 0.94, 1.07 23 1.00 0.95, 1.06 Accidents 0 2,980 Reference 3,285 Reference ≥1 50 1.01 0.97, 1.05 78 1.01 0.98, 1.04

Abbreviation: CI, confidence interval.

a

Adjusted for birth weight, gestational age, birth order, breastfeeding, secondhand smoke, maternal place of birth, maternal educational level, type of hospital at birth, income of household head, and Rutter score at 7 years of age.

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