What Is Known
- Studies have identified infants born late preterm (gestational age of 34–36 weeks) at risk for growth failure during the first 2 years of life.
- Infants with cystic fibrosis are at risk of being born premature, and thus at risk for growth failure.
- Growth during the first 2 years of life is important for infants with cystic fibrosis as higher weight-for-length percentiles at age 2 years are correlated with improved lung function.
- We do not have any information on growth for infants with cystic fibrosis who are born late-premature.
What Is New
- Infants with cystic fibrosis born late-preterm are more likely to require higher calorie dense formulas and feeding tubes during the first 2 years of life.
- Despite the use of higher calorie formula and feeding tubes, these infants are still at risk for growth failure by 2 years of age as evidenced by lower weight-for-length percentiles compared with their term peers.
- More research is needed in addressing growth failure in these infants and valuable interventions that can be utilized earlier in life.
Adequate nutrition within the first 2 years of life plays a crucial role in neurocognitive development and long-term health outcomes for healthy infants (1,2). Late preterm infants [born 34–36 weeks’ gestation (3)] are at increased risk for growth failure and higher morbidity and mortality compared with term infants, which is thought to be multifactorial (3–7). This phenomenon in healthy preterm infants appears to be especially apparent within the first 2 years of life.
The same is true regarding infants born with cystic fibrosis (CF). Growth during the first 2 years of life is strongly associated with improved pulmonary function later in life (8–10). Infants who fall below the 10th percentile for weight-for-age (WFA) at 2 years of age have both decreased lung function and survival (11). In a recent retrospective analysis of data collected from the CF Foundation Patient Registry (CFFPR), children who maintained a BMI >50th percentile each year from birth until age 6 years had the highest pulmonary lung function (FEV1) at 6 years of age when compared with children who did not maintain this BMI percentile (12). Infants with CF who have pancreatic insufficiency are at increased risk of stunted growth, defined as a length z score of less than 1.28 or <10th percentile during the first 2 years of life (13). On the basis of these studies and others, the Cystic Fibrosis Foundation Subcommittee on Growth and Nutrition has set a goal for all children born with CF to achieve a weight-for-length (WFL) status of at least the 50th percentile by 2 years of age and to monitor for pancreatic insufficiency regularly (14).
In 2016 in the CFFPR, 619 children were diagnosed with CF and of those, 88.8% were born at term and 11.3% were born preterm (15). A 2016 retrospective analysis looking at birth certificates and hospital discharges after birth for children born between 1996 and 2013 found a 3-fold increased risk of being born premature if the infant had CF, although growth was not assessed for this study (16). It is unknown if children with CF have different risks for growth failure when born late preterm compared with children with CF born at full-term.
The goal of the present study is to describe a retrospective cohort of infants born with CF during the years 2010 to 2013 and registered in the CFFPR to compare their WFL percentiles at 2 years of age. We hypothesized that those children in this CF cohort born late preterm, when compared with subjects with CF born at term, would have a greater likelihood of falling below the 50th percentile for WFL and below the 10th percentile for WFL percentile at 2 years of age.
We used data from the CFFPR (17). Inclusion criteria for this study included children diagnosed with CF and entered into the registry from 2010 to 2013 and who had anthropometric data through 2 years of age. We chose these specific years to assure that we captured children diagnosed via the newborn screen in all states across the United States as this is when CF screening was included in all newborn screens. We excluded all infants born before 34 weeks’ gestational age. Children with meconium ileus were also excluded, as they represent a population with more comorbidities and complications related to intestinal function and growth (18,19).
We determined the following for all infants in this cohort:
- 1. Sex.
- 2. Race (Caucasian vs non-Caucasian).
- 3. Insurance (private vs public).
- 4. Number of hospitalizations in the first 2 years of life.
- 5. Use of pancreatic enzymes (as a surrogate for the presence of exocrine pancreatic insufficiency).
- 6. CF transmembrane conductance regulator (CFTR) mutation type (I–III vs. IV–V).
- 7. Any encounters for Pseudomonas aeruginosa infection in the first 2 years of life.
- 8. Use of inhaled tobramycin and/or dornase alfa in the first 2 years of life.
- 9. Use of high caloric density formula.
- 10. Placement of a feeding tube (nasogastric, nasojejunal, gastrostomy, or gastrojejunostomy).
- 11. Growth parameters:
- a. Birth weight.
- b. Birth length.
- c. Annualized weight.
- d. Annualized length.
- e. Annualized WFL percentiles.
Annualized metrics are entered into the CFFPR as the mean of the highest values in each quartile for the patient-year. Centers for Disease Control (CDC) growth charts percentiles were used rather than World Health Organization (WHO) charts as previous studies have shown a higher percentage of children falling within the underweight category for WFL on the CDC growth curve rather than WHO (20). A separate study identified similar improved lung function at age 18 years for those children that were ≥50th percentile for WFL on the WHO and CDC growth charts at age 2 years (21). For these reasons, we chose to use the CDC growth charts. We chose to not exclude infants born very low birth weight (VLBW) defined as those <1500 g as they are not excluded from the CDC growth charts that were used as to assess growth in this study. Institutional review board approval was obtained through the Indiana University School of Medicine Institutional Review board.
Demographic variables were analyzed using chi-square tests for categorical variables and Student t-tests for continuous variables. Bivariate analyses were conducted using chi-square tests for categorical variables, in order to test associations between individual variables and our outcomes of interest (WFL <10 percentile and <50 percentile at age 2 years). Multivariate logistic regression models were built using WFL <50th percentile at age 2 years and WFL <10th percentile at age 2 years as our outcome/dependent variables. WFL was used rather than WFA or length-for-age (LFA) as these are better indicators of overall growth status and the CF Foundation identifies a WFL goal at 2 years of age rather than LFA or WFA. We did look at LFA and WFA <10% and 50% to identify any differences overall but did not include this in our model. Independent variables were selected, a priori, based on those believed to contribute to disease severity or progression of disease (use of pancreatic enzymes, number of hospitalizations, Pseudomonas colonization, severe mutations [class I, II, or III]), ways to deliver additional calories (use of a feeding tube and higher calorie nutrition), as well as demographic variables, including sex and insurance type. We chose to not stratify and analyze based on sex as the CDC growth charts are already separated by sex. The results would be misleading. Significance was defined as a P value <0.05. Statistical analyses were conducted using SPSS statistics 25 (IBM, New York, NY) and SAS v9.4 (SAS Institute, Cary, NC). All analytic assumptions were verified, with log-transformations being used where necessary for nonlinear continuous variables and Fisher exact tests for categorical variables when cell counts were small. Collinearity between measures in the multivariable model were also tested, with variance inflation factors (VIFs) being considered as significantly collinear if >5.
A total of 2955 infants were born from 2010 to 2013 with CF. Among these, 231 (8%) were born late preterm (Fig. 1). Three hundred and ninety-seven were excluded as they were <34 weeks’ gestation. A total of 379 infants were excluded for meconium ileus (17% of which were late preterm). Patients were also excluded if they were missing WFL data at 2 years of age. The final number for analysis included 1834 term infants and 137 late preterm infants (Fig. 1).
Demographics are displayed in Table 1 and were fairly similar between term and late preterm infants. A significantly larger percentage of infants born late preterm were hospitalized during the first 2 years compared with term infants (53% compared with 44%, P = 0.041). A significantly higher percentage of late preterm infants used dornase alfa within the first 2 years of life compared with term infants (63% vs 55%, P = 0.049). Among the excluded infants, the only significant difference for late preterm infants was a higher percentage of Pseudomonas infection in those excluded versus included (36% vs 14%) with a P value of 0.011. Otherwise, there were no statistically significant differences in the included versus excluded infants in either late preterm or term groups.
Some important differences were noted between the 2 groups. Late preterm infants were significantly more likely to have feeding tubes (ie, nasogastric, nasojejunal, gastric, or gastrojejunal) and higher calorie supplemental feeds (22+ kilocalorie/ounce formula or fortified breast milk) compared with term infants at any point in the first 2 years of life (Table 1). Twenty-two percentage of late preterm infants had a feeding tube compared with only 13% of term infants (P = 0.006) and 87% late preterm were supplemented with higher calorie formula compared with 79% in the term group (P = 0.035).
Late preterm infants weighed less at birth compared with infants born term. The average birth weight for late preterm infants was 2.5 kg (standard deviation [SD] 0.4) compared with 3.2 kg (SD 0.5) for term infants (P < 0.001). The average age at diagnosis for both term and late preterm was 25 days of life.
Overall, late preterm infants with CF were smaller in regards to WFA, LFA, and WFL measurements at 2 years of age compared with term infants with CF. The mean WFA percentile for late preterm infants was 36 (SD 27.2) compared with 44.9 (SD 27.6) for term infants (P = 0.002). The mean LFA percentile was 33.4 (SD 24.4) for late preterm and 44.4 (SD 25.9) for term (P < 0.001). Lastly, the mean WFL percentile was 48.7 (SD 29.1) for late preterm and 55.7 (SD 27.4) for term infants (P = 0.023). Table 2 assesses the likelihood that subject below the 50th and 10th percentiles at 2 years of age for WFA, LFA, and WFL. Late preterm infants overall were more likely to fall below the 10th percentile for WFA, LFA, and WFL at 2 years of age.
Growth patterns across the first few years are depicted in Figure 2. Of note, late preterm infants did not have complete catch-up growth over the first 2 years of life. Late preterm infants with CF grew in length faster than term infants with CF over the first 2 years (Fig. 2B). This has been described in studies of non-CF late peterm infants (5,22).
Whenever controlling for demographic and clinical factors with our logistic regression models, we found late preterm infants to be more likely to be below the 10th percentile for WFL at 2 years of age compared with term peers. We also discovered demographic and clinical factors, such as female sex, use of public insurance, and use of feeding tubes to be significant (Table 3).
We describe a retrospective cohort study using the CFPPR to determine the effect of late preterm status on growth parameters at 2 years of age in children with CF. We found that late preterm infants with CF are at higher risk for growth failure at 2 years of age compared with term peers with CF, despite the use of higher calorie formulas, feeding tubes, and more frequent hospitalizations. Previous studies have demonstrated a degree of catch-up growth around 18 months for late preterm infants compared with term without CF and increased growth in length for late preterm infants compared with term (5,22). Our study displayed similar results in that the infants in our group showed some catch-up growth but not complete and they grew longer faster than term infants with CF. This helps to explain Figure 2C in which the WFL decreases across the 2 years. Figure 2B supports the 2009 study by Santos et al in that there is a steeper upward trajectory in length between years 1 and 2 for late preterm infants with CF. This is mirrored in the Santos et al (22) study involving comparison of length for late preterm and term infants without CF.
Studies in late preterm infants without CF have used different outcome measures but reported similar findings of delayed catch-up growth during the first 2 years of life. In a large retrospective cohort study, late preterm infants were more likely to display growth failure (defined by a fall of 2 or more SDs in WFA) at 6, 12 and 18 months, although not statistically significant at 18 months of age (5). A separate retrospective study showed preterm infants were 3 times more likely to have a weight-for-length (WFL) z-score less than −2 by 2 years of age when compared with their term peers (22). However, late preterm infants also gained an average of 61 g more and grew 1 cm more in length compared with term infants during the first year of life, indicating that most late preterm infants show signs of catch-up growth over the first year of life. This was not the case between years 1 and 2, indicating that the growth response in these children is likely to be complex.
The CF Foundation recommends all children ages 1 to 2 years with growth deficits be offered more intensive treatment, including behavioral interventions and use of nutritional supplements (14). Although it is likely that feeding tubes were used in response to poor growth, the indication for the feeding tubes is not recorded in the CFFPR. There is a chance that the feeding tubes were used for oral-motor dysfunction, which occurs more frequently in all late preterm infants and is a major reason for re-hospitalization after birth (7,23). Additionally, we did not quantify the amount of increased calories, or the precise length of time they were used.
Girls (both late preterm and term) were at the highest risk of being below the 50th and 10th percentiles at 2 years of age compared with their male counterparts (Table 3). Studies have demonstrated worse pulmonary and nutritional outcomes for girls with CF as well as overall survival compared with boys (24–27). A 2017 study by Munck et al (13) found no difference between length or weight z-scores between girls and boys with CF during the first 2 years of life. The BONUS trial described lower length and weight measurements for male infants during the first year of life compared with female infants with CF (28). Social constructs between men and women likely play a large reason why females with CF end up with poorer nutritional and health outcomes overall (29).
This study has several important limitations. Due to the observational nature of this study, we cannot imply causality between late prematurity and WFL at age 2 years. This data set captures 2 years of data and while 40% of term and late preterm infants were below the 50th percentile for WFL at 2 years of age, it is not to say that they would not catch up and surpass this mark after 2 years of age. The use of linear growth percentiles (WFA, WFL, and LFA) are important nutrition measures in CF but not quite as accurate as skin-fold thickness, caloric intake, IGF-1 measurement or body fat percentage, which are better indicators of nutritional status than anthropomorphic measurements in healthy children and children with chronic diseases (30). Also, as with any national registry, there may be missing data points, inaccurate entry, missing important dietary history, and records that could explain slower weight gain and whether or not birth weight is always documented in the registry. Annualized data points rather than individual encounter level data. Although encounter level data may give more data points on the growth chart trends, they are fraught with individual error or poor measuring and entering data into the registry. We believe that the use of annualized data points show an overall trend and finally, where these infants fall in regards to WFL at age 2. Finally, most of the data are provided through clinics and hospital records, so patients who receive most of their care outside these settings (eg, at home) would not be included in our data set.
Ongoing prospective studies, such as the BONUS trial found that infants born with CF (term and preterm) diagnosed by newborn screen, who were followed periodically for the first year of life achieved normal weight by 12 months of age, despite having lower birth weights overall. In this study, only 13.6% of infants were less than the 10 percentile for WFA and 24% were less than the 10 percentile for length at 1 year of age (28). A similar study is warranted for late preterm infants.
In summary, late preterm infants with CF are at risk for poorer nutrition status over the first 2 years of life as evidenced by low WFL percentiles compared with term infants with CF. Despite the more frequent use of feeding tubes, re-hospitalizations, and higher calorie formulas, they show more significant risk than term.
The authors would like to thank the Cystic Fibrosis Foundation for the use of CF Foundation Patient Registry (CFFPR) data to conduct this study. Additionally, we would like to thank the patients, care providers, and clinic coordinators at CF Centers throughout the United States for their contributions to the CF Foundation Patient Registry.
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