Determination of Pubertal Status in Youths With Type 1 Diabetes Using Height Velocity and Trajectories

Abstract

Context

Assessment of pubertal change is important for the management of chronic pediatric diseases, such as type 1 diabetes. Physical and/or laboratory assessments of pubertal status are often unavailable, impractical, or costly.

Objective

To develop and validate a practical and objective method to assess pubertal status using longitudinal linear growth in youths with type 1 diabetes.

Design, Participants, and Outcome Measurements

Participants (n = 123) were part of a 2-year study assessing continuous glucose monitoring in youths with type 1 diabetes at a tertiary diabetes center. Pubertal status at visits was assigned by a tiered approach using clinical Tanner staging or indicators of pubertal maturation from the electronic medical record when available. For other visits, independent evaluations of height velocities and growth chart trajectories provided data for pubertal status assignments. Sensitivity analysis confirmed the validity of the pubertal status assignments.

Results

The sample (50% female, 95% white) had a mean ± SD age of 12.7 ± 2.7 years, diabetes duration of 6.0 ± 3.6 years, and hemoglobin A1c of 7.9 ± 0.8%. Of 985 study visits, 50% received a pubertal status assignment based on clinical Tanner staging, 29% on additional medical record review, and 22% on an evaluation of height velocity and growth chart trajectory. For the sensitivity analysis, pubertal status assignments based on height velocity and growth chart trajectory matched clinical Tanner staging in 87% of visits.

Conclusions

Our practical and objective method to assess pubertal status based on height velocity and growth chart trajectory highlights growth as a reliable and objective bioassay for pubertal onset, status, and progression.

Height velocity and growth chart trajectory provided data for pubertal status assignments in 123 youths with type 1 diabetes over 2 years with 87% sensitivity compared with clinical Tanner staging.

Puberty is a crucial developmental period for both physical and psychological maturation. Hormonal changes during the pubertal transition have been shown to affect the management of chronic diseases. In particular, insulin requirements for youths with type 1 diabetes increase substantially during puberty with the development of physiologic insulin resistance (1–5). In epidemiologic studies in adults, pubertal timing has been associated with subsequent cardiovascular disease, malignancies, and depression (6–9). Thus, pubertal timing appears to be an important trait with effects on various aspects of adolescent and adult health and is often a data point of interest in clinical research studies and in the routine delivery of clinical care.

Pubertal onset is a clinical diagnosis, marked by the emergence of breast buds in girls and testicular enlargement in boys (10). After these initial events, the pubertal growth spurt occurs, reflecting the influence of sex steroids and growth hormone (11). Pubertal onset and progression can be assessed by Tanner staging and confirmed with costly laboratory evaluation, although laboratory assessment is rarely necessary in the absence of suspected pathology.

In youths with type 1 diabetes, determining pubertal onset and progression can inform timely insulin adjustments and provide an opportunity for anticipatory guidance. Current clinical care guidelines for youths with type 1 diabetes recommend annual physical examinations with pubertal staging, which may miss the timely capture of pubertal onset or transitions (12). Similarly, in large population-based observational studies, regular and frequent assessment of Tanner staging is often not practical or feasible. Other measures of pubertal timing, such as age at menarche in girls and age at voice deepening in boys, reflect late stages of puberty and do not provide information about the full range of pubertal maturation (7, 10). In contrast, anthropometric data are easily collected during clinical and research visits and are widely available in electronic medical records.

In this report, we sought to develop a reliable, biological method for assessing pubertal status and progression using linear growth data in a longitudinal study of youths with type 1 diabetes. We used routinely collected height data to assign pubertal status (prepubertal, pubertal, and postpubertal), and we validated this methodology against clinical Tanner staging within this study sample.

Subjects and Methods

Study participants and design

Study participants were part of a 2-year study assessing continuous glucose monitoring technology in youths with type 1 diabetes at a tertiary diabetes center (13, 14). Briefly, eligibility criteria included youths 8 to 17 years of age with diabetes duration of at least 1 year. Participants with severe medical or psychiatric disorders were excluded. All study participants/parents provided written informed assent/consent. The study protocol was approved by the Institutional Review Board. No study procedures occurred prior to approval and consent.

In general, study visits were coupled with quarterly clinical diabetes visits with physical examinations, including Tanner staging, performed by experienced pediatric endocrinologists. Anthropometric measures were obtained by trained clinical assistants at each visit according to routine clinical practice with repeat measurements often when clinical discrepancies arose (e.g., apparent loss of height or excessive weight gain or loss); height and weight were measured using a calibrated electronic stadiometer and digital scale, respectively. We calculated age- and sex-adjusted body mass index z-scores derived from reference data from the Centers for Disease Control and Prevention growth charts (15). Height and weight were plotted using Centers for Disease Control and Prevention growth charts (15).

Pubertal status assignments

Pubertal assignments at each visit resulted from a four-tiered approach as follows: Tier A, Tanner staging by a clinician within 6 to 12 months before the study visit; Tier B, Tanner staging from additional visits; Tier C, additional indicators of pubertal maturation reported in the electronic medical record; and Tier D, evaluation of height velocity and growth chart trajectory. Tanner staging was based on breast maturation for girls and genital maturation for boys (16, 17). Tanner stage 1 was considered prepubertal, Tanner stages 2 through 4 were considered pubertal, and Tanner stage 5 was considered postpubertal.

Tier A

If Tanner staging was performed on the day of the visit or within the 6 months prior to the visit, pubertal status was based on that Tanner stage. If Tanner staging was performed >6 months but within 12 months prior to the study visit and the participant was Tanner stage 2 or 3 at that visit, a status of “pubertal” was assigned because progression from midpuberty to postpuberty (Tanner stage 5) typically occurs over a period of >1 year (18–21).

Tier B

Tier B pubertal status assignment was based on Tanner stage data from the medical record that did not meet Tier A criteria but that met one of the following criteria: (i) If the most proximal previous Tanner stage was the same as the most proximal subsequent Tanner stage, then pubertal status was based on that Tanner stage. For this criterion, Tanner stages 2, 3, and 4 were considered equal (all pubertal). (ii) If the most proximal subsequent Tanner stage was 1, then prepubertal status was assigned. (iii) If the most proximal previous Tanner stage was 5, then postpubertal status was assigned.

Tier C

If pubertal status was not assigned by Tier A or B criteria, the participant’s medical record was reviewed to ascertain additional indicators of pubertal status (e.g., age at menarche). If the provider documented an assessment of the participant’s pubertal status based upon a combined clinical and physical evaluation, which included previous Tanner staging, current adrenarchal status, and growth, that pubertal status was assigned (e.g., “early or mid-pubertal status” was assigned as pubertal). For comments detailing “completion of linear growth,” the postpubertal status was assigned. The tempo of pubertal progression was also used to guide Tier C pubertal status assignments. In boys, if Tanner stage 3 or 4 genitalia was documented more than 3 or 2 years prior to the study visit, respectively, then “post-pubertal” status was assigned (20). In girls, visits that occurred within a 6-month period of menarche were assigned “pubertal” status, and visits that occurred >18 months after menarche were assigned “post-pubertal” status (21). Girls who underwent menarche 6 to 18 months prior to the visit underwent height velocity and growth chart assessment in Tier D.

Tier D

Visits in which participants were not assigned a pubertal status by Tier A, B, or C criteria underwent calculation of height velocity between visits and an independent review of their growth chart. Calculated height velocities between visits were transformed to annualized height velocities in cm/y. Annualized height velocities were compared with those of a normative sample from the Bone Mineral Density in Childhood Study; height velocities ≥5.9 cm/y for male participants and ≥6.6 cm/y for female participants corresponded to the median ages of pubertal onset of 11.1 years and 10.4 years in male and female participants, respectively (22). These velocities were defined as the pubertal threshold. For participants for whom all Tier D visits had a height velocity less than the pubertal threshold, pubertal status assignments from Tiers A through C were used to assign either a pre- or postpubertal status. For the six participants for whom there were no other Tier assignments available for reference, the participant’s age and growth chart trajectory were used to guide an assignment of either pre- or postpubertal status. To minimize measurement error, participants were considered pubertal if their height velocities matched the pubertal threshold for two velocities across three sequential visits and were considered pre- or postpubertal if their height velocities were less than the pubertal threshold for three sequential visits. For two participants, categorization of the height velocities at the first study visits was inconsistent, so a single weighted height velocity was calculated to assign pubertal status. For another two participants, only two visits were available for height velocity calculation, so a single height velocity was used to assign pubertal status.

On growth chart review, a physician visually evaluated each participant’s growth chart to inspect changes in slope and overall trajectory. Figure 1 illustrates a growth chart example from prepubertal to pubertal status and subsequently to postpubertal status. When there were discrepancies between the pubertal status assignments from height velocity and growth chart review, pubertal status assignments resulted from adjudication procedures by a pediatric endocrinologist, a pediatrician, and a statistician based on anthropometric measures including height velocity, age of menarche when appropriate, and growth chart review (n = 45 visits, 5%).

Figure 1.

Growth curve example of growth trajectories during pubertal maturation, including height trajectories typically observed during prepubertal, pubertal, and postpubertal maturation in a female participant.

Confirming pubertal statuses

After tiered pubertal assignments were made, data from all participants underwent review to assess any inconsistencies, such as regression of pubertal status. Visits with inconsistent assignments (n = 5 visits) underwent adjudication.

A sensitivity analysis was performed to assess the validity of calculated height velocities and growth chart reviews. A statistician randomly selected 20 participants with physical Tanner staging data who represented the range of pubertal maturation from a computer-generated list to undergo Tier D evaluation. These data were provided to another coauthor for the independent sensitivity analysis.

Statistical analyses

Descriptive statistics for demographic and clinical data are given as mean ± SD or percentages. Sensitivity analysis provided the means to assess concordance of pubertal status assignments by height velocity calculation and growth curve review with Tanner staging by physical examination. SAS software (version 9.4; SAS Institute, Inc., Cary, NC) was used for all analyses.

Results

Baseline participant characteristics

A total of 123 participants with type 1 diabetes were included. Collectively, the participants had 985 visits over a 2-year period. In general, height measurements were obtained at clinic visits every 3 months; the shortest time interval between height measurements was 6 to 8 weeks. Clinical characteristics are summarized in Table 1. At the first visit, participants (50% female, 95% white) had a mean age of 12.7 ± 2.7 years, a duration of diabetes of 6.0 ± 3.6 years, and a hemoglobin A1c of 7.9 ± 0.8% (63 ± 9 mmol/mol).

Table 1.

Participant Characteristics

Demographics (N = 123)	Mean ± SD	% (n)
Male sex		50 (62)
Age, y	12.7 ± 2.7
Race/ethnicity, % white		95 (117)
z-BMI, SDS	0.5 ± 1.0
Number of visits	8.0 ± 1.5
Diabetes parameters
Duration of diabetes, y	6.0 ± 3.6
Total insulin dose, U/kg/d	0.9 ± 0.2
HbA1c, %	7.9 ± 0.8 (63 ± 9 mmol/mol)

Abbreviations: HbA1c, hemoglobin A1c; U, units insulin; z-BMI, body mass index z-score.

Pubertal status assignments

Pubertal status assignments based on the four-tiered approach are summarized in Table 2. Of the 985 study visits, 36% received a pubertal status assignment based on Tanner staging within 6 to 12 months of the study visit (Tier A). Another 14% received pubertal status assignments based on Tanner staging at additional visits (Tier B). An additional 29% received pubertal status assignments based on medical record descriptions of the pubertal status (Tier C), and pubertal status of the final 22% was based on height velocity calculations and growth chart review (Tier D).

Table 2.

Categories of Pubertal Status Assignments and Final Pubertal Status for All Visits

Total Study Visits (N = 985)	n	% Total Visits
Tier A: Tanner staging by clinician	351	36
Tier B: Tanner staging at additional visits	134	14
Previous and next pubertal stage are equal	29	2.9
Next pubertal stage is prepubertal	13	1.3
Previous pubertal stage is postpubertal	92	9.3
Tier C: Additional medical record review	282	29
Provider assessment	90	9.1
Pubertal progression	192	19
Tier D: Height velocity calculation and growth chart review	218	22
Height velocity and growth chart congruent	173	18
Adjudication review (discrepancy)	45	4.6
Final pubertal status assignments
Prepubertal (Tanner 1)	213	22
Pubertal (Tanner 2–4)	382	39
Postpubertal (Tanner 5)	390	40

Tier D assignments based on height velocity calculations and independent review of the growth chart matched in 79% (173 out of 218) of study visits. Pubertal assignments for the remaining 45 visits, involving 16 participants, underwent adjudication. In 24 of the 45 visits, discrepancies were attributed to brief periods of seemingly irregular growth, likely due to errors in height measurements [Fig. 2(a) and 2(b)]. In 16 of the 45 visits, discrepancies were seen during the transition periods from prepubertal to pubertal status or pubertal to postpubertal status [Fig. 2(c) and 2(d)]. The remaining five visits, involving two participants, required adjudication because pubertal statuses appeared to regress from postpubertal to pubertal over time. In one participant, four visits were reclassified as postpubertal, and in the other participant, one visit was reclassified as pubertal. In the former participant, growth chart review confirmed linear growth deceleration and attainment of adult stature. Upon careful scrutiny of the medical history, the initial misclassification of postpubertal regression to pubertal status was likely secondary to the onset of disordered eating behaviors and the resulting low estrogen state. The reclassification of the latter participant likely resulted from measurement error that appeared to show growth deceleration, whereas subsequent measurements yielded ongoing growth. Additionally, timing of menarche confirmed ongoing pubertal maturation.

Figure 2.

Growth curves illustrating discrepancies between pubertal status assignments by height velocity calculation and growth curve review. (a and b) A boy (a) and a girl (b) in whom the discrepancy is attributed to brief periods of seemingly irregular growth, likely due to errors in height measurements. (c and d) A boy (c) and a girl (d) in whom the discrepancy is attributed to transition periods between pubertal statuses. Arrows depict study visits without clinical Tanner staging that required pubertal status assignments by height velocity (HV) calculation and growth curve review. Pubertal status assignments by each method are shown in the tables for each growth curve, with “Adjudication Assignment” as the final pubertal status assigned after adjudication.

After adjudications and determining the final pubertal status assignments of all 985 visits, participants at 213 visits (22%) were classified as prepubertal, 382 (39%) as pubertal, and 390 (40%) as postpubertal (Table 2).

Sensitivity analysis

To validate our methodology of assigning pubertal status based on height velocity calculation and growth chart review, 20 participants with available clinical Tanner staging data were randomly identified to represent the range of pubertal maturation and transitions. At the baseline visit, eight participants were prepubertal, with four progressing to pubertal status during the study follow-up; 10 participants were pubertal, with four progressing to postpubertal status; and two participants were postpubertal. Pubertal status was assigned (Tier D) by calculation of height velocity and independent review of growth charts, encompassing 167 study visits.

Final pubertal status assignments based upon a combination of height velocity calculations, growth chart reviews, and clinical adjudications matched the clinical Tanner staging in 87% of visits (146 out of 167). For the remaining 13% of visits (n = 21), all discrepancies between pubertal status assignments based on our methodology and clinical Tanner staging occurred during transition periods from prepubertal to pubertal status (n = 6) or pubertal to postpubertal status (n = 15).

Discussion

Tanner staging of breasts and genital maturation in girls and boys, respectively, guides the clinical evaluation of pubertal onset and progression (10). In youths with type 1 diabetes, clinical guidelines from the International Society for Pediatric and Adolescent Diabetes recommend physical examinations with pubertal staging once yearly (12). Thus, Tanner staging data may not be available more than once annually in routine clinical care as well as in large population-based observational studies. Insulin requirements for the management of type 1 diabetes vary according to pubertal status; thus, accurate determination of pubertal onset and progression may allow timely insulin dosing adjustments and anticipatory guidance on glycemic control for youths and their parents. In contrast to Tanner staging, anthropometric measures, including height, are a routine component of most if not all clinical visits and can be easily obtained during clinical and research study visits.

Using linear growth data collected longitudinally, we present a practical method to assess pubertal onset and progression that demonstrates 87% sensitivity against clinical Tanner staging. By showing the strong correlation between height velocity and clinical sexual maturation, our method confirms that linear growth can be used as an objective biomarker of pubertal status in youths with type 1 diabetes.

Prior studies have proposed both vertical growth measures and additional physical traits as indicators of pubertal timing. Markers of vertical growth, including peak height velocity (23–25), height difference in standard deviations (26, 27), and percentage of height achieved of the predicted adult stature (28, 29), have been used as indicators of pubertal timing. To avoid the intrusion of the breast and genital physical examination, epidemiological studies have used recall age of menarche in female participants (7, 30) and age at voice breaking in male participants (7, 27). However, most of these vertical growth and physical trait indicators occur during mid- or late puberty, often years after pubertal onset (10). Other studies have used self-assessment of pubertal status using standardized cartoon figures of Tanner stages, but this is a subjective measure with limited accuracy that may be especially challenging for younger children transitioning from Tanner stage 1 to 2 (31–33). Thus, there is no easily accessible and reliable indicator for pubertal onset, status, or progression other than physical examination, which is often deemed unpleasant by developing adolescents. The recent report of age-based reference ranges for annual height velocity in a diverse sample of US children with regular assessment of sexual maturation (22) has allowed us to demonstrate linear growth as a reliable, objective measure of pubertal onset, status, and progression in a sample of youths with type 1 diabetes receiving routine clinical care.

Our results highlight the limited availability of pubertal Tanner staging in a tertiary pediatric endocrinology clinic because only 36% of visits had a documented Tanner stage. Indeed, despite concurrent study visits regarding continuous glucose monitoring use, these participants did not receive additional Tanner staging. The general medical and psychosocial demands of diabetes care take priority and encompass the majority of time during clinic visits, leaving little time to assess pubertal maturation. Because pediatric diabetes guidelines recommend Tanner staging annually (12), it is understandable that Tanner staging may not be done at every quarterly visit. Nonetheless, it is important to understand and anticipate the biological and psychological changes of puberty for clinical care. During puberty, youths with type 1 diabetes undergo hormonal changes that result in insulin resistance (1, 34, 35). This leads to an increase in insulin requirements and changing patterns of insulin delivery needs (e.g., the “dawn phenomenon”) (4, 36, 37).

Strengths of our study include the universal availability of growth data and sufficient clinical Tanner staging by pediatric endocrinologists that capture pubertal onset and progression over a 2-year longitudinal period. An additional strength is the use of the practical metric of height velocity, which has the potential to be automatically calculated by electronic medical record systems with the input of a single algebraic equation, similar to automated body mass index calculations. Furthermore, evaluation of growth curves is a visual inspection method based on pattern recognition, as detailed in Figures 1 and 2, that can be completed on the order of minutes per participant.

Limitations of our study include the predominantly white population, which may limit the generalizability of our findings. However, the height velocity standards used to guide pubertal status assignments were from a large multiethnic population–based study of US youths (22). Thus, it is possible that the 87% sensitivity of our method may be even higher in a study sample that is more ethnically comparable to this reference population. In general, height velocities were annualized from quarterly height assessments in our study, whereas the frequency of height assessments in clinical practice and population-based observational studies may be more limited to a biannual or annual basis. Although more frequent height assessments may better capture linear growth trajectories, our method could be applied to clinical evaluations or studies with less frequent height assessments. We acknowledge that single height measurements may be prone to error and may likely account for discrepancies in pubertal status assignments between height velocity and growth chart evaluations. However, our dual evaluation of the height velocity and the growth chart trajectory identified such irregularities for further evaluation and adjudication to assign pubertal status.

The 13% of study visits with discrepancies between pubertal status assignments using our methodology and clinical Tanner staging were all during transition periods between pubertal statuses (i.e., prepubertal to pubertal or pubertal to postpubertal), with the majority of discrepancies occurring during the latter transition. Physiology during pubertal transition periods involves gradual changes; thus, we would expect these misclassifications to have modest biological impact. An additional limitation of our study may reflect the inclusion of only youths with type 1 diabetes. However, a recent publication reports that youths with type 1 diabetes undergo puberty at the expected time and attain adult heights that correspond to their genetic potential (38). Thus, if pubertal timing and linear growth in youths with type 1 diabetes are comparable to the general population, our methodology could be applied to the general population. Future studies can validate our approach in other samples of youth.

In summary, puberty is a critical event with significant impacts on the management of pediatric chronic diseases, such as type 1 diabetes, and on health risks during adolescence and adulthood. Physical and biochemical assessments of pubertal status have either limited feasibility or undue costs in clinical and research settings, highlighting the need for an easily available, reliable, and objective measure of pubertal status. Our report of a practical method to assess pubertal status based on evaluations of height velocity and growth chart trajectory highlights linear growth as a reliable bioassay for pubertal onset, status, and progression. The assessment of linear growth in youths in this and in future studies can harness the power of data collection in the electronic medical record to advance our understanding of puberty and associated health outcomes.