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. 2021 Oct 19;16(10):e0258731. doi: 10.1371/journal.pone.0258731

Effects of cyproheptadine on body weight gain in children with nonorganic failure to thrive in Taiwan: A hospital-based retrospective study

Yi-Chun Lin 1,2, Hung-Rong Yen 1,3, Fuu-Jen Tsai 3,4,5, Chung-Hsing Wang 5,6, Lung-Chang Chien 7, An-Chyi Chen 5,*, Ro-Ting Lin 2,*
Editor: Tai-Heng Chen8
PMCID: PMC8525746  PMID: 34665812

Abstract

Failure to thrive (FTT) impairs the expected normal physical growth of children. This study aimed to evaluate the effects of cyproheptadine hydrochloride on growth parameters in prepubertal children with FTT. The medical records of prepubertal children who were newly diagnosed with FTT at China Medical University Hospital between 2007 and 2016 were retrospectively examined. The patients were divided into two groups depending on whether they had (T-group) or had not (NT-group) received cyproheptadine hydrochloride (0.3 mg/kg daily) for at least 14 days. The mean length of the treatment period was 97.22 days (range: 14–532 days). Weight, height, and body mass index were adjusted for age using the median values in the growth charts for Taiwanese boys and girls as the reference. A total of 788 patients aged 3–11 years were enrolled, 50 in the T-group and 738 in the NT-group. No statistically significant difference in the median age-adjusted weight value was noted between the T-group and NT-group during the follow up period. In the T-group, age-adjusted weight and body mass index were inversely associated with age (P <0.001, P <0.001) and positively associated with medication duration (P = 0.026, P = 0.04). Our findings underscore the positive association between cyproheptadine hydrochloride treatment and weight gain among prepubertal children. Further prospective clinical studies with a. longer and consistent treatment course is warranted.

Introduction

Children with growth retardation account for 5–10% of pediatric outpatient visits [1, 2]. Failure to thrive (FTT) describes a state of undernutrition among children who are unable to maintain the expected growth velocity according to age- and sex-specific growth charts [3]. FTT is associated with long-term negative health and developmental consequences, including short stature, cognitive disorders, behavioral abnormalities [4], and higher risk of respiratory syncytial virus infection and hospitalization [5]. Thus, it is immensely important for children to obtain sufficient nutrition for their growth and development from birth until the end of puberty [6].

FTT can be categorized into two types—namely, organic and nonorganic. Organic FTT describes children with poor growth and underlying medical conditions, whereas nonorganic FTT refers to children with poor growth but without underlying medical conditions [3]. More than 86% of FTT cases in hospitalized children have nonorganic etiologies, and this percentage is likely to be higher in the outpatient setting [3].

Treatment for nonorganic FTT focuses on behavioral and environmental modifications to stimulate the appetite of children and consequently increase their oral food intake [7]. Behavioral interventions include the provision of health education about correct nutritional concepts and appropriate feeding skills to children and their caregivers, whereas environmental modifications include the provision of suitable dining environments, atmospheres, and appliances to patients [8]. Behavioral and environmental modifications as well as food supplementation are applied as first-line therapy, albeit often in vain [8, 9]. Therefore, pharmacological stimulation is employed as adjunctive therapy [10, 11].

Studies have shown that histaminergic and serotonergic receptor systems modulate feeding behaviors [1214]. Furthermore, findings from numerous studies support the use of appetite stimulants such as cyproheptadine hydrochloride (CH) for the promotion of weight gain in children with or without underlying medical conditions who exhibit poor growth [7, 11, 1519]. Nonetheless, owing to procedural differences among the studies, it is difficult to make comparisons, draw conclusions, and establish clear guidelines for CH administration. For instance, the drug dosage, treatment duration, and age of the study subjects (prepubertal children and adolescents) differed in three previous randomized clinical trials of nonorganic FTT [11, 18, 19]. Additionally, children possess different feeding skills at different ages and exhibit different growth trends before versus during puberty [2022]. Hence, we retrospectively investigated the effects of CH use on weight in prepubertal children with nonorganic FTT who were treated at a hospital in central Taiwan from 2007 to 2017.

Materials and methods

Study design

Data were collected from the records of children treated for nonorganic FTT at the pediatric endocrinology and gastroenterology outpatient clinic at China Medical University Hospital Children’s Hospital Medical Center (CMUCHMC) in Taichung, Taiwan, between January 1, 2007 and December 31, 2017. CMUCHMC is not only a tertiary university-affiliated medical center but also a medical research and education institution in central Taiwan.

Study subjects and variables

The electronic medical records of children diagnosed with FTT at CMUH between January 1, 2007 and December 31, 2017 were retrospectively reviewed. The collected data included date of birth, date of encounter, diagnosis, treatment, body height (BH), body weight (BW), puberty stage, medical prescriptions, maternal height, paternal height, birth weight, and gestational age at birth.

The inclusion criteria were as follows: (i) boys aged 3–11 years and girls aged 3–10 years at the first visit; (ii) a diagnosis satisfying the criteria of codes 783.41, 783.40, and 783.43 of the International Classification of Disease, 9th Revision, Clinical Modification, as well as other FTT-related codes (as ancillary documents); and (iii) BW below the 3rd percentile or body mass index (BMI) below the 5th percentile (as derived from growth charts and matched for age and sex) at the first visit. Children <3 years-old at the first visit were excluded owing to the difficulty in distinguishing organic FTT from nonorganic FTT in this age group according to a recent report [23]. The exclusion criteria were as follows: (i) diagnosis of pathological FTT; (ii) diagnosis of a congenital or organic disease; (iii) long-term (>3 months) use of appetite stimulants other than CH including traditional Chinese medicines; (iv) intake of CH (0.3 mg/kg/day) for <14 days; (v) essential information missing from the electronic medical records (e.g., BW, BH, and puberty onset as indicated by breast, testicular, or public hair development, voice change, and menarche).

Because our study was retrospective, the allocation of treatment modalities was based on previous choices made by patients and their parents in consultation with their physicians. The data for patients who either did not receive CH or received CH at a dosage of 0.3 mg/kg/day for >14 days were retrieved, and BW, BH, and medication duration were assessed. The patient’s height was measured in the hospital using a wall-mounted stadiometer. Maternal height and paternal height were recorded during outpatient follow-up. BMI was calculated as weight divided by height squared (kg/m2).

Statistical analysis

The heights, weights, and BMIs of the patients in our study were normalized for age using the standard values in the growth charts for Taiwanese children and adolescents as the reference. The growth charts are based on World Health Organization and health-related physical fitness standards [22]. Each value for each patient was matched to the median chart value for a child of the same age and sex as the patient. The patient value was then divided by the corresponding chart value, and the product was multiplied by 100. The adjusted values are referred to as %BH, %BW, and %BMI. Higher percentages indicate greater concurrence with standard values. Owing to unobtainable raw data, we were unable to calculate the standard deviation scores for height, weight, and BMI. The t-test was used to compare continuous variables between the control and treatment groups. The effects of medication duration on height, weight, and BMI were analyzed using linear mixed models with a first-order autoregressive structure, taking time, age, sex, and treatment group into account. All statistical analyses were performed using SAS version 9.4 software (SAS Institute, Cary, NC).

Ethical considerations

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki and was approved by the Research Ethics Committee of China Medical University and CMUH [CMUH106-REC3-069(CR-2)]. The retrospective analysis in this study was performed using routine clinical and laboratory data from electronic medical records at CMUH, and the data were anonymously accessed. Hence, the institutional review board waived the need for informed consent forms.

Results

A total of 4,096 patients with a diagnosis related to FTT were initially enrolled. Subsequently, 2,914 patients treated with medications other than CH and 394 patients diagnosed with pathological FTT or a congenital or organic disease were excluded. Ultimately, 788 eligible patients were included in this study. They were divided into two groups: those who had received CH treatment (0.3 mg/kg/day, the T-group, N = 50) and those who had not (the NT-group, N = 738) (Fig 1).

Fig 1. Flow chart.

Fig 1

Characteristics of patients with FTT

The number of outpatient clinic visits was higher in the T-group than in the NT-group. Most patients (38%) in the T-group had visited the clinic >5 times compared with none in the NT-group (Table 1). More than half (57.9%) of the patients the NT-group had visited the clinic only twice.

Table 1. Visiting status of subjects with failure to thrive.

Number of visits NT-group T-group ALL
N (%) N (%) N (%)
1 62 (8.4) 0 (0) 62 (7.9)
2 427 (57.9) 13 (26) 440 (55.8)
3 183 (24.8) 5 (10) 188 (23.9)
4 66 (8.9) 13 (26) 79 (10.0)
≥5 0 (0) 19 (38) 19 (2.4)

The demographic and anthropometric characteristics of the study groups at the first visit are summarized in Table 2. The mean age, height, and weight for all patients at diagnosis were 7.3 ± 2.4 years, 111.0 ± 13.5 cm, and 17.7 ± 4.5 kg, respectively. Additionally, the mean BMI, maternal height, and paternal height were 14.2 ± 1.1, 155.4 ± 4.8 cm, and 168.0 ± 5.5 cm, respectively. Mean age, height, weight, and BMI were significantly lower in the T-group than in the NT-group (P = 0.0032, 0.0218, 0.0023, and 0.0067, respectively). The differences in height, weight, and BMI between the two groups were the result of the difference in mean age. Thus, we normalized heights, weights, and BMIs for age using the sex-matched median values new growth charts for Taiwanese children and adolescents as the reference. After adjustment, no differences in %BH, %BW, or %BMI were observed between the T-group and NT-groups (Table 2).

Table 2. Comparison of the demographic and anthropometric characteristics of the failure to thrive groups at the first visit.

Variable ALL NT-group T-group P value
N = 788 N = 738 N = 50
All patients
    Age, year 7.3 ± 2.4 7.4 ± 2.4 6.3 ± 2.5 0.0032**
    Height, cm 111.0 ± 13.5 111.3 ± 13.4 106.8 ± 14.3 0.0218**
    Weight, kg 17.7 ± 4.5 17.8 ± 4.5 15.9 ± 4.1 0.0023**
    BMI 14.2 ± 1.1 14.2 ± 1.1 13.8 ± 1.1 0.0067**
Standard value for girls (N = 362) a
    Height, cm 119.8 ± 12.8 120.0 ± 12.6 115.6 ± 16.0 0.1578
    Weight, kg 23.2 ± 5.7 23.3 ± 5.7 21.7 ± 6.9 0.2498
    BMI 15.9 ± 0.6 15.9 ± 0.6 15.8 ± 0.7 0.4865
Standard value for boys (N = 426) a
    Height, cm 123.3 ± 14.2 123.9 ± 14.1 116.4 ± 14.2 0.0040****
    Weight, kg 25.3 ± 6.9 25.6 ± 6.9 22.0 ± 6.4 0.0051**
    BMI 16.3 ± 0.8 16.3 ± 0.8 15.9 ± 0.7 0.0066**
Age-adjusted value for all patients b
    Height, % 91.2 ± 3.5 91.1 ± 3.5 91.9 ± 3.1 0.1275
    Weight, % 73.2 ± 5.8 73.2 ± 5.7 73.3 ± 6.7 0.8616
    BMI, % 88.3 ± 7.3 88.3 ± 7.3 87.0 ± 8.1 0.2091
Paternal height, cm 168.0 ± 5.5 168.0 ± 5.5 168.1 ± 5.3 0.9569
Maternal height, cm 155.4 ± 4.8 155.4 ± 4.8 155.8 ± 4.7 0.5892
Mid-parental height c , cm 162.5 ± 7.6 162.4 ± 7.6 164.0 ± 7.0 0.1616

All data are expressed as mean ± standard deviation. The t-test was used to compare the continuous variables between the control and treatment groups.

aThe standard values for height, weight, and BMI were derived from the growth charts for Taiwanese boys and girls at ages corresponding to those of the patients. The chart values at the 50th percentile was used.

bThe percentages for height, weight, and BMI were calculated as follows: patient value ÷ standard value × 100.

CCalculated the mid-parental height by adding 6.5 cm to the average of both parents’ heights for boys or subtracting 6.5 cm from the average of both parents’ heights for girls.

**P <0.05.

BMI, body mass index.

Table 3 presents the modeling results for the effects of selected determinants on health outcomes in all subjects with FTT. The median %BW value did not differ significantly between the T-group and NT-group. Nonetheless, as the medication duration increased, median %BW and %BMI increased in a linear manner; both were inversely associated with age (P <0.001, P <0.001) and positively associated with medication duration (P = 0.026, P = 0.04).

Table 3. Estimated effects of determinants on health outcomes in all subjects (N = 788).

Determinant %BH %BW %BMI
Estimate P value Estimate P value Estimate P value
Intercept 89.955 <0.001** 78.126 <0.001** 96.569 <0.001**
Time 0.000 0.141 0.001 <0.001** 0.001 0.004**
Treatmenta vs. controlb 0.719 0.719 -0.333 0.686 -1.863 0.047**
Male vs. female 0.495 0.043** 1.096 0.009 ** 0.507 0.291
Age 0.102 0.044** -0.783 <0.001** -1.150 <0.001**
Medication duration 0.016 0.261 0.089 0.026** 0.088 0.040**

aTreatment: cyproheptadine hydrochloride (0.3 mg/kg/day, >14 days).

bControl: no treatment.

**P <0.05.

BH, body height; BW, body weight; BMI, body mass index.

Table 4 presents the modeling results for the effects of selected determinants on health outcomes in patients with FTT who received CH treatment. In this group, as in all patients, median %BW and %BMI were inversely associated with age (P <0.001, P <0.001) and positively and linearly associated with medication duration (P<0.001, P = 0.006). Each additional day of CH treatment increased the median %BW value by 0.121 units. This is equivalent to a weight gain of 26.45 g/day, which was calculated by multiplying the daily weight gain unit (0.121) by the average standard weight of the T-group (21.86 kg). The following formula was used to determine the average standard weight:

21.7×362girls+22.0×426boys788total

Table 4. Estimated effects of determinants on health outcomes in the T-group (N = 50).

Determinant %BH %BW %BMI
Estimate P value Estimate P value Estimate P value
Intercept 91.614 <0.001** 81.851 <0.001** 97.588 <0.001**
Time -0.001 0.292 0.00005 0.974 0.002 0.269
Male vs. female 0.164 0.857 1.263 0.511 1.275 0.462
Age 0.024 0.889 -1.359 <0.001** -1.675 <0.001**
Medication duration 0.022 0.017** 0.121 <0.001** 0.095 0.006**

The T-group received cyproheptadine hydrochloride (0.3 mg/kg/day, >14days).

**P <0.05.

BH, body height; BW, body weight; BMI, body mass index.

Additionally, extending the medication duration increased the median %BMI value by 0.095 units per day. Nevertheless, we were unable to assess whether the linear relationship between weight gain velocity and medication duration could extend beyond 4 months. It was because the medication duration in our study varied widely, ranging from 14 days to 532 days, and the number of subjects was insufficient for stratified analysis.

Discussion

Main findings

Our findings reveal a positive association between CH intake and weight gain among prepubertal children. We found that continuous intake of CH (0.3 mg/kg/day) for at least 14 days (mean: 3.24 months) increased the weight gain velocity and BMI in a linear fashion among prepubertal children (age range: 3–11 years) with mild-to-moderate wasting (60–74% of the median weight standard) but without medical conditions.

Possible explanation

Low doses of CH (0.1–0.3 mg/kg/day) have been shown to have a pronounced effect on weight gain in children (S1 Table). Increasing the CH dose from 0.1 to 0.3 mg/kg/day increased weight gain velocity from 11.66 to 22.32 g/day and accelerated the attainment of normal weight in children in random control trials. The CH dosage for prepubertal children with non-organic FTT was the same in our study and that by Rerksuppaphol et al. [19]; however, the mean daily weight gain in our study was higher (26.45 g/day vs. 22.32 g/day) (S1 Fig). The results of Nemati et al. [24] suggest that CH loses effectiveness at higher doses: in mice fed 5, 10, or 20 mg/kg of CH per day, weight and food intake increased, did not change, or decreased, respectively. The exact mechanism underlying the effects of low-dose CH on weight gain in children is not entirely understood; hence, future studies on this matter are warranted.

The present study revealed a positive linear relationship between median %BW during treatment and medication duration. In a previous randomized controlled trial, CH use led to rapid and early weight gain in children with growth deficiencies, particularly in the first 4 months of treatment [25]. According to a chart review study on CH for stimulant-induced weight loss, the median time to a response is 65 days [26]. Considerable weight gain occurred within 2 weeks in the study by Rerksuppaphol et al. [19], but required 1–4 months in the study by Sant’Anna et al. [7]. Mahachoklertwattana et al. [11] showed that CH therapy increased weight within 2 months and that weight gain velocity proportionately declined as the length of the treatment increased. In our study, the mean CH duration was 97.22 days (3.24 months), which echoes the findings of the abovementioned studies on children with poor growth. Nevertheless, the length of the treatment in our study varied widely, ranging from at least 14 days to 532 days. We did not have a sufficient number of case subjects for a stratified analysis to determine whether the linear relationship between weight gain velocity and medication duration extended beyond 4 months. Clinical trials are required to explore this matter.

As summarized in a retrospective review, the side effects of CH are fairly benign in children with feeding problems [7]. Reported side effects such as tachycardia, constipation, diarrhea, irritability, and sleepiness are resolved by decreasing the dosage of CH or discontinuing the treatment [7, 27, 28]. Because side effects directly affect CH dosage and treatment duration, they also indirectly affect weight gain. Future research exploring the potential intermediary role of side effects on the association between CH treatment and body weight is suggested.

Possible mechanism

Although unresolved, CH most likely promotes weight gain by acting as an appetite stimulant, thereby increasing calorie intake and causing weight gain. Two hypotheses have been proposed to explain this phenomenon. The first hypothesis suggests that CH increases appetite by directly activating the hypothalamic appetite center [19, 29]. This has been shown in animal models and has clinical relevance as the effects of CH on 5-HT2 and H1 receptors [12, 14, 30, 31] are also observed in humans [15, 32, 33]. Additionally, Comer et al. [34] showed that CH increases the number of eating occasions, suggesting that its actions may be more related to postprandial satiety/hunger signaling than to a food reward pathway.

The second hypothesis is based on the effects of CH on gastric activity [27, 28]. Previous studies using animal models revealed that CH decreases gastric tone and increases gastric compliance via 5-HT2A and 2B receptors, resulting in gastric fundic relaxation [35, 36]. Others found that CH barricade of serotonin receptors in animal intestines diminished the secretory effects of serotonin, thereby increasing feeding volume and calorie intake [37, 38]. It has been suggested that CH therapy increases growth velocity in underweight children by increasing the serum level of insulin-like growth factor-I (IGF-I) [11]. However, Razzaghy-Azar et al. [39] dispute this contention: in their study, the IGF-1 level was only slightly elevated and still below the normal range after CH therapy. Thus, further molecular studies of additional pathways are warranted.

Study strengths and limitations

CMUCHMC, the site of our study, is not only one of the first National Children’s Hospitals recognized by the Ministry of Health and Welfare in Taiwan but also the largest children’s hospital in central Taiwan. It receives a large number of visits (e.g., 179,832 clinic visits in 2016) and is very representative of the demography in central Taiwan. Therefore, the strengths of this study included its large sample size and real-world use of CH. Additionally, the longitudinal dataset allowed us to assess the effects of CH over time in a diverse group of patients. Lastly, the weight gain (26.45 g/day) achieved in our study using 0.3 mg/kg/day was greater than that reported in previous studies, as was the speed with which normal weight was attained.

The present study also has some limitations. First, it had a retrospective study design that involved a chart review; hence, the causal relationship between CH treatment and weight gain cannot be confirmed. Second, the electronic medical records used for this study did not include information on socioeconomic status (e.g., household income) or confounding factors (e.g., disease activity, use of other drugs in other hospitals or clinics during the observation period, health education assessment). A previous study showed that a low household income could limit access to adequate diets, particularly for older children, and indicated that parents and caregivers might require dietary guidance to ensure sufficient quantity and quality of the foods eaten at home and to foster healthy eating habits among children [40]. Owing to the lack of information on household income in the present study, we might have underestimated the benefits of CH treatment. Although we did not consider prior behavioral or environmental interventions in the present study, we note that health education, which includes information on behavioral and environmental modification, is the first-line treatment for children with non-organic FTT at our hospital. Hence, variations in health behaviors among the study participants should be small. However, previous studies have shown that health education often fails to reach its expected goal [8, 9].

Third, it was difficult to accurately exclude subjects with feeding disorders or functional gastrointestinal disorders via a retrospective review of medical records only. Pediatric feeding disorders are common: their reported percentages in children with and without delayed development are 25% and 80%, respectively. The consequences of feeding disorders such as growth failure can be severe [41]. Because severity potentially affects weight gain velocity, we might have underestimated the benefits of CH treatment.

Fourth, the children in the T-group visited our hospital and hence may have received more medical attention than did those with fewer visits. To compensate, we incorporated the number of visits into the time variable of our linear model, as shown in Table 4. Finally, because most of the patients in our study, which was conducted in central Taiwan, were Han Chinese, its generalizability to other ethnic groups may be limited.

Conclusion

The use of CH (0.3 mg/kg/day, >14 days) is beneficial for prepubertal children with non-organic FTT in terms of promoting weight gain and quick attainment of normal weight.

Supporting information

S1 Table. Cyproheptadine use in underweight and/or malnourished children.

(PDF)

S1 Fig. Mean weight gain velocity in underweight and/or malnourished children with cyproheptadine hydrochloride.

(PDF)

Data Availability

Data cannot be shared publicly because of routine clinical and laboratory data from electronic medical records at the CMUH. Data are available from the CMUH Institutional Data Access (contact via website: https://www.cmuh.cmu.edu.tw/NewsInfo/NewsArticle?no=3568 or email: bdc@mail.cmuh.org.tw) for researchers who meet the criteria for access to confidential data.

Funding Statement

The study was supported by grants from the China Medical University Hospital (DMR-107-154). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Tai-Heng Chen

6 May 2021

PONE-D-21-05718

Effects of cyproheptadine on body weight gain in children with nonorganic failure to thrive in Taiwan: a hospital-based retrospective study

PLOS ONE

Dear Dr. Lin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 20 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: I Don't Know

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Lin, et al. submit a manuscript reporting a retrospective review of 788 children seen in the China Medical University Hospital for failure to thrive between 2007 and 2016. Fifty children received cyproheptadine in an attempt to improve weight gain, while the remaining 738 were untreated. The investigators compared measures of height, weight, and body mass index at baseline. Standardized measures adjusting for age showed that there was no difference between the groups at baseline. Based on modeling, the investigators identified a linear relationship between the duration of cyproheptadine treatment and measures of weight and BMI.

Specific comments:

1. Line 37: It is unclear what the authors mean by “%BH, %BW, and %BMI (50th percentile for age and sex)” It does not appear to mean percentiles for height, weight, and BMI. Does it mean the percentage of the 50th percentile for these measures? If so, this is an unusual way to express the data. The authors should analyze their data in terms of percentiles or SD scores.

2. Lines 39-40: It is unclear whether the authors are referring to measures obtained at baseline or at follow up.

3. Lines 45 and 202: What is meant by “we determined by consensus that CH was helpful…”

4. Line 59: Recommend “…children hospitalized with FTT have nonorganic etiologies…”

5. Lines 68-70 and 70-72: These two passages are redundant

6. Various places in the manuscript: Reference is made to “prepuberty children.” This should be “prepubertal children.”

7. Various places in the manuscript: Cyproheptadine is abbreviated to CH, but this is not done consistently.

8. Lines 142-145: The fact that the majority of patients in the NT group only had two visits to the clinic while the T group visited 5 or more times is a confounder because the increased medical attention and focus on weight may have altered feeding practices.

9. Table 2: What is “standard height/weight/BMI?”

10. Line 203: I think the authors mean 0.3 mg/kg daily.

11. In addition to the unusual expression of relative body measures, the authors do not discuss the changes in body weight in individual patients. The best approach would be to compare the change in height, weight, and BMI percentiles or SD scores in the T group vs. the NT group. It is not clear why they did not do this.

12. It is not clear what this study adds to an already fairly extensive literature.

13. Additional data would be informative, including the dose used, duration of treatment, and pubertal status.

Reviewer #2: The manuscript by Yi-Chun Lin and colleagues describes a retrospective cohort study looking at the effect of cyproheptadine on growth parameters in pre-pubertal children with non-organic failure to thrive. They showed that the group treated with cyproheptadine had statistically significant association with medication duration and %BW and %BMI. They were able to include a large number of patients compared to prior studies, but were limited due to its retrospective nature and multiple possible confounders.

Major comments/suggestions/questions:

Were the investigators able to gather information about prior behavioral or environmental interventions as well as nutritional supplements? Since these are common first line treatments it would be interesting to see if these patients had previously or concurrently used these treatments.

Since there have been many randomized control trials, it should be emphasized how this single center retrospective review adds to the known body of literature. One aspect that could be emphasized is the larger sample size. Another could be the real-world use of cyprohepatidine.

Table 1 – The title could be made more clear with listing the number of visits as opposed to "visiting status" and visit 1, etc

Z scores for weight and height and BMI for age should be used and compared between groups. This is the standard to assess nutritional status in children. There is not much utility in comparing weights and heights without adjusting for age and sex. Also, it would great to include mid-parental height and accounted for it if possible.

Table 3 and 4 are confusing and require more explanation in the results section. There appears to be a negative association between treatment vs control on % BMI in table 3 based on how it is displayed. Could these results be better shown with a graph?

The results section mentions an “equivalent weight gain of 26.43g/day,” but it is unclear how that number was obtained. Please explain how that was calculated.

It would be beneficial to include the dose and duration of cyproheptadine use in the methods section or as part of the results.

Were side effects reported and could they be included in this manuscript? Regardless of that data being available, there should also be a discussion of potential side effects of using cyproheptadine in the discussion section.

In the discussion it is mentioned that the higher the CH dose the child received the more weight velocity was attained, but the comparison between this real-world study and the RCTs can not lead to this conclusion. It might be inferred from the comparison but unless a full study is done, the conclusion the authors draw can not be made. This should be changed in the discussion.

Table 5 in general seems unnecessary and could be moved to being a supplemental table.

Minor comments:

De-identified data should be made available upon request

The increased number of clinic visits seen between the treatment groups should also be included as a possible confounder. The more frequent visits might indicate that the parents are more likely to be motivated to try an intervention and use other therapies.

Reviewer #3: This retrospective study examines the effects of cyproheptadine on weight gain and vertical growth in a small cohort of 50 children ages 3-11 diagnosed with nonorganic failure to thrive treated with cyproheptadine between 2007-2017 in an academic tertiary care center in Taiwan. These children are compared to a fairly large untreated cohort. Using “Linear Mixed Modeling”, the authors conclude that cyproheptadine improved %BMI and %BW in children with nonorganic failure to thrive. I think this has potential to support published data on the benefits of cyproheptadine for this specific age group.

Major Critiques:

1. This study does not add significant new contributions to the body of literature, as numerous published articles (including a systematic review and two prospective trials appropriately cited in the text) highlight the beneficial effects of cyproheptadine on growth. The authors cite differences in dosing and population standardization in prior studies as reasons to publish this data, but the cohort has significant age variation, and the authors do not clearly delineate if/what variation in cyproheptadine dosing was used in the patients in their cohort. Of note, suggestions for dosing exist for cyproheptadine as an appetite stimulant in medication dosing reference resources such as UpToDate.

Minor Critiques:

- Few minor grammatical errors should be addressed throughout the manuscript

PAGE 8, line 104: Recommend defining what qualifies as a “long-term medicines”. Would this be other appetite stimulants? Stimulant medications for ADHD that might suppress appetite? Would a multivitamin or other medication such as polyethylene glycol that would most likely be unrelated to growth exclude a patient?

PAGE 9, lines 117-119: Recommend including what specific statistical tests were used to compare treatment groups (ie t-test is cited in Table 2). Additional description of how “Linear Mixed Models” were used for statistical analysis is extremely important, as the conclusions are completely based on this analysis.

PAGE 13, Table 2: Very “busy” table. Could simplify to facilitate interpretation by excluding “N” columns and instead include the “N” data below column or row headings, and combine the Mean SD columns into Mean (SD)

PAGE 14, Table 3: This table does not clearly communicate desire results. Interpreting results in this format is not intuitive. Unclear what “Intercept” and “Time” refer to. Better represented graphically?

PAGE 15, Table 4: Similarly, a confusing table. Unclear what “Intercept” and “Time” refer to. Better represented graphically?

PAGE 15, Line 202-206: It is unclear where the outcomes stated in the main findings (0.3 mg of CH x14 days) is associated with increased BW gain and BMI are represented in the figures/tables.

PAGE 16, Line 211-213: Discussion about dose of cyproheptadine for appetite stimulation and subsequent reference to Table 5 is disjointed. Strongly recommend rewording.

PAGE 16, Table 5: The dosing of cyproheptadine should be introduced in the “Methods” section. The first mention of the dose of cyproheptadine occurs in the “Discussion section”

Figure 1: This figure is not cited in the text. The figure shows patients treated with traditional Chinese medicine were excluded, but this is not mentioned in the body of the text as one of the exclusion criteria

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Oct 19;16(10):e0258731. doi: 10.1371/journal.pone.0258731.r002

Author response to Decision Letter 0


29 Jun 2021

Dear Editors and Reviewers,

We wish to resubmit our manuscript titled “Effects of cyproheptadine on body weight gain in children with nonorganic failure to thrive in Taiwan: a hospital-based retrospective study” (PONE-D-21-05718R1) to PLOS One for further consideration.

We thank the reviewers for their in-depth reading of our manuscript and their insightful comments. We have carefully considered their remarks and have modified our manuscript accordingly. As a result, we believe that our manuscript is much improved and hopefully now acceptable for publication in your journal.

Our point by point responses to the reviewers’ comments and questions are below.

We look forward to hearing from you soon.

Sincerely yours,

Ro-Ting Lin

Associate Professor of College of Public Health, China Medical University, Taiwan

Attachment

Submitted filename: Response_20210618.pdf

Decision Letter 1

Tai-Heng Chen

28 Jul 2021

PONE-D-21-05718R1

Effects of cyproheptadine on body weight gain in children with nonorganic failure to thrive in Taiwan: a hospital-based retrospective study

PLOS ONE

Dear Dr. Lin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 11 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. Table 4 indicates that medication duration is positively associated with gains in %BW and %BMI. Could there be a selection bias here that explains this relationship? Those who had a good response might be more likely to continue medication use, while those who did not respond might abandon the treatment early.

2. Lines 211-213: The inability to assess the relationship beyond 4 months of treatment should be stated in the Results section as well.

Reviewer #2: In this revised version they have responded to many of the comments from reviewers but the following are comments that should still be addressed prior to acceptance of the manuscript:

Major comments/suggestions:

It would be more useful to have a mid-parental height as opposed to seeing the maternal and paternal heights separately

Please include units for variables in Table 2. For example in rows for standard value for girls/boys should include (cm, kg) and for age-adjusted values should include (%). It is described in footnote, but should also be included in the table.

Tables 3 and 4 are difficult to interpret alone without the explanation found in the text. Please display this information graphically in addition to showing the tables. This will make the data easier to interpret and will be visually more impactful.

Minor comments:

Line 99 is missing closed parenthesis

Line 101 should say “choices made by patients and their parents in consultation with their physicians”.

The formula for the calculation of average standard weight should be included in the methods and not the results section.

It would be nice if the new figure comparing this study with the others was included as a supplemental figure and referenced in the discussion section. It seems a shame for this figure to be only for the reviewers.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Oct 19;16(10):e0258731. doi: 10.1371/journal.pone.0258731.r004

Author response to Decision Letter 1


12 Aug 2021

Dear Reviewers,

We would like to thank you for reviewing our revised manuscript and giving us insightful comments. We have carefully reviewed your suggestions, responded to your comments, and revised our manuscript. As a result, we believe that our revised manuscript is much improved and hopefully now acceptable. We have attached a point-by-point response file in response to your comments for your review. We look forward to hearing from you soon.

Sincerely yours,

Ro-Ting Lin

Associate Professor of College of Public Health, China Medical University, Taiwan

Attachment

Submitted filename: Response_20210812.pdf

Decision Letter 2

Tai-Heng Chen

5 Oct 2021

Effects of cyproheptadine on body weight gain in children with nonorganic failure to thrive in Taiwan: a hospital-based retrospective study

PONE-D-21-05718R2

Dear Dr. Lin,

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: (No Response)

Reviewer #2: The manuscript by Yi-Chun Lin and colleagues describes a retrospective cohort study looking at the effect of cyproheptadine on growth parameters in pre-pubertal children with non-organic failure to thrive. They showed that the group treated with cyproheptadine had statistically significant association with medication duration and %BW and %BMI. They were able to include a large number of patients compared to prior studies, but were limited due to its retrospective nature and multiple possible confounders.

In this revised version they have responded to all of the comments from reviewers. The analysis is done in an appropriate manner and the data is presented in a clear manner.

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Reviewer #1: No

Reviewer #2: No

Acceptance letter

Tai-Heng Chen

11 Oct 2021

PONE-D-21-05718R2

Effects of cyproheptadine on body weight gain in children with nonorganic failure to thrive in Taiwan: a hospital-based retrospective study

Dear Dr. Lin:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

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on behalf of

Dr. Tai-Heng Chen

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Cyproheptadine use in underweight and/or malnourished children.

    (PDF)

    S1 Fig. Mean weight gain velocity in underweight and/or malnourished children with cyproheptadine hydrochloride.

    (PDF)

    Attachment

    Submitted filename: Response_20210618.pdf

    Attachment

    Submitted filename: Response_20210812.pdf

    Data Availability Statement

    Data cannot be shared publicly because of routine clinical and laboratory data from electronic medical records at the CMUH. Data are available from the CMUH Institutional Data Access (contact via website: https://www.cmuh.cmu.edu.tw/NewsInfo/NewsArticle?no=3568 or email: bdc@mail.cmuh.org.tw) for researchers who meet the criteria for access to confidential data.


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