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. Author manuscript; available in PMC: 2020 Aug 1.
Published in final edited form as: Neurogastroenterol Motil. 2019 May 26;31(8):e13650. doi: 10.1111/nmo.13650

Pharyngeal contractile and regulatory characteristics are distinct during nutritive oral stimulus in preterm-born infants: Implications for clinical and research applications

Varsha Prabhakar 1, Kathryn A Hasenstab 1, Erika Osborn 1, Lai Wei 2, Sudarshan R Jadcherla 1,3
PMCID: PMC6793932  NIHMSID: NIHMS1052355  PMID: 31131508

Abstract

Background:

Maturation of pharyngeal swallowing during neonatal oral feeding is unknown. Our objective was to evaluate pharyngeal functioning using high-resolution manometry (HRM) during nutritive oral stimulus and test the hypothesis that pharyngeal contractility and regulation are distinct in preterm-born infants.

Methods:

High-resolution manometry data during oral milk feeding were analyzed for pharyngeal contractile (PhCI, mm Hg cm s) and regulatory (number and frequency of pharyngeal contractions and bursts, pharyngeal activity-to-quiescence ratio, upper esophageal sphincter nadir pressure) characteristics in 23 preterm (<38 weeks’ gestation) and 18 full-term-born infants at term maturation. Mixed linear models and stepwise regression methods were used.

Results:

Despite more oral feeding experiences (P < 0.05), preterm infants (vs full-term), consumed less milk volume (P < 0.001), had lesser pharyngeal contractions within bursts (P = 0.04), lower pharyngeal contraction frequency (P < 0.01), and lower pharyngeal activity (P = 0.03), but higher PhCI per individual contraction (P = 0.01). PhCI is higher for longer PMA (P < 0.05), higher UES nadir pressures (P < 0.05), and lower pharyngeal contraction frequency (P < 0.05).

Conclusions:

Nutritive oral milk stimulus provoked pharyngeal contractility characteristics is distinct in preterm-born. Despite more oral nutritive experiences, preterm infants had underdeveloped excitatory and inhibitory rhythmic activity. Cranial nerve IX and X effects on sensory-motor responses and feedback (excitation-inhibitory rhythm regulation) remain immature among preterm-born even at full-term maturational status. We speculate the relationship between PhCI and UES regulatory activity contributes to the observed differences in preterm and full-term infants.

Keywords: high resolution manometry, maturation, nutritive oral feeding, pharyngeal contractile integral, preterm infants

1 |. INTRODUCTION

Technological advances improve survival rates among preterm-born infants but eating and swallowing difficulties and dysphagia-related morbidities are on the rise.1,2 Poor coordination of sucking, swallowing, and respiratory patterns likely contributes to feeding difficulties and aerodigestive symptoms in infants, leading to prolonged hospitalization amidst parent/provider anxiety.3–9 Coordination of pharyngeal and upper esophageal sphincter (UES) function and regulation is critical during swallowing to steer bolus away from the airway.10 Preterm-born infants are likely to experience poor pharyngeal clearance and higher deglutition apnea rates even when healthy.11 In adults, weaker pharyngeal contractions have been associated with poor pharyngeal clearance and dysphagia12,13 while hyperpharyngeal contractility has been known to occur during effortful swallows.14–16 Research on pharyngeal contractility and its relationship to UES function in infants is limited.

We have previously used water perfusion manometry to study pharyngeal rhythms, UES, and esophageal peristalsis in preterm infants.17,18 However, this method is limited to one pressure sensor in the pharyngeal region. In adults, high-resolution manometry (HRM) techniques have made it possible to study both the regulatory and contractile functions in greater detail with the presence of multiple sensors in the pharyngeal region. Application of HRM in infants will further our understanding of their pharyngeal swallowing physiology.19 Contractility of the pharynx and its relationship with UES relaxation pressures is unknown in preterm and full-term infants. Discerning differences between these groups of infants will enable us to understand the significance of in utero maturation for successful nutritive swallowing abilities. The aim of this study was to compare pharyngeal and UES activity characteristics of preterm and full-term-born infants to identify how differences in intrauterine and extrauterine maturation affect the functions of pharynx. We hypothesize that preterm infants are distinct from full-term-born infants in pharyngeal function (contractility and regulation) at identical postnatal maturation and examine whether this translates to their nutritive milk intake efficiency.

2 |. METHODS

2.1 |. Subjects

The study includes 41 (18 male) infants admitted to Nationwide Children’s Hospital, Columbus, OH, USA, referred for swallowing evaluation. Both preterm (<38 weeks’ gestation) and full-term infants were evaluated at full-term postmenstrual age (≥40 weeks). These infants were either partially or fully oral feeding during the time of study. Exclusion criteria included gastrointestinal or congenital anomalies. Institutional Review Board approval and written informed parental consent were obtained in compliance with the Health Insurance Portability and Accountability Act. Patient safety was continuously monitored by the physician and a registered nurse at the crib side during the study procedures.

2.2 |. Manometry methods and protocol

A solid state 6 Fr catheter containing 25 unidirectional pressure sensors evenly spaced 1 cm apart (UniTip High-Resolution Catheter, Unisensor USA) was connected to a HRM recording system (Solar GI, Laborie Medical Technologies) using a data acquisition rate of 50 Hz. Experimental protocol included a 3-minute oral feeding challenge initiated after infants adjusted to the catheter’s presence.20

2.3 |. Data analysis

High-resolution manometry data from the studies were imported in.CSV format from MMS analysis software (version 9.5, Laborie Medical Technologies) into Python (V 3.6.2). Swallow detection and analysis algorithms were used as previously published.19 User inputs to the algorithms included time windows of oral feeding and the identification of pharyngeal and UES regions on the pharyngo-esophageal topography plots.19

2.4 |. Definitions of analytical variables of interest

Pharyngeal activity was analyzed by (a) contractile characteristics and (b) regulatory characteristics Figure 1. Contractility was analyzed through the pharyngeal contractile integral (PhCI, mm Hg cm s), which is a 3-dimensional measure of contractile amplitude >20 mm Hg over the length of pharynx and duration of each contraction. Pharyngeal regulatory characteristics quantify the patterns and type of contractions. Contractions were either solitary or occurring in pharyngeal bursts. Pharyngeal bursts were defined as a continuous rhythmic contractile pattern with 2 or more pharyngeal contractions occurring within 2 seconds of each other. Regulatory characteristics included number of pharyngeal contractions, % contractile activity (duration of total pharyngeal activity which is the sum of solitary and burst durations/duration of feed), activity-to-quiescence ratio (duration of total pharyngeal activity/duration of pharyngeal inactivity), frequency of contractions (1/duration between contractions, Hz), number of pharyngeal bursts, number of pharyngeal contractions per burst, duration of burst(s), and burst activity (duration of bursts/duration of feed). UES relaxation was considered when UES pressure dropped >50% from UES baseline and UES nadir as the lowest pressure in UES for each pharyngeal contraction.21 Constraint programming with hill climbing search22 was used to develop an algorithm to identify UES relaxation and UES nadir pressures. This was performed using pharyngeal contraction times identified by automatic swallow detection,19 UES length, and 50% UES relaxation thresholds as constraints. In addition to the variables obtained from HRM data, volumes (mL) consumed during the oral feeding session were also recorded.

FIGURE 1.

FIGURE 1

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Data Analysis of high-resolution manometry (HRM) Pharyngo-Esophageal Pressure Topography Plot during Oral Feeding. C1-C6 represent 6 pharyngeal contractions. B1 & B2 represent duration of bursts; C, duration of contraction, s; IBQ, interburst quiescence duration, s; ℓ, Pharyngeal length, cm. R, duration of UES relaxation, s; Regulatory characteristics: number of pharyngeal contractions (C1-C6); % contractile activity ((B1 + B2)/(IBQ + B1 + B2)), %; activity-to-quiescence ratio ((B1 + B2)/IBQ); frequency of contractions (6/(IBQ + B1 + B2)), Hz; Contractile characteristic: PhCI (DC × ℓ × average contractile amplitude), mm Hg cm s

2.5 |. Statistical analysis

This was a mechanistic observational study involving preterm- and full-term-born infants. Kruskal-Wallis and chi-square tests were used to compare demographic characteristics between full-term and preterm infants. Pharyngeal and UES activity characteristics were compared between the two groups using linear mixed effects models in SAS version 9.3 (SAS Institute). A stepwise linear regression approach was developed in R version 3.3.0 to identify predictors of PhCI by first examining bivariate models (predictor and outcome) and presenting a full model (UES nadir pressure and pharyngeal regulatory characteristics). Data are presented as median (IQR), mean ± SE, or β ± SE. A P-value of <0.05 was considered statistically significant.

3 |. RESULTS

3.1 |. Demographics

Overall, 2126 pharyngeal contractions recorded from 354 pharyngeal contractile bursts and 536 solitary contractions were analyzed. Subjects included 18 preterm-born and 23 full-term-born infants evaluated at term PMA. Demographic characteristics at birth and time of evaluation are shown (Table 1). The pharyngeal length at evaluation was 3.3 (3.1–3.8) cm for preterm-born infants and 3.2 (3–3.3) cm for full-term-born infants (P = 0.09). During the 3-minute oral feeding challenge test, consumption (mL) was lesser in preterm-born infants 6 (3–10) mL vs full-term-born infants 11 (9.5–16.5) mL, (P = 0.01).

TABLE 1.

Demographic characteristics of preterm and full-term-born infants

Characteristics Variable Preterm (N = 23) Full-term (N = 18) P-Value
Birth characteristics GA, weeks 32.8 (28.1–34.4) 39 (38.2–41.2) <0.0001
Weight, kg 2.1 (1.1–2.7) 3.5 (3.3–3.6) 0.0001
Length, cm 43.3 (37–47.4) 51 (48.3–53.3) 0.0002
Head circumference, cm 29.9 (25.5–31) 34.5 (33–36) 0.0001
Time of study characteristics PMA, weeks 42.5-(40.7–44.1) 43.7 (41.1–45.4) 0.1
Weight, kg 3.7 (3.5–4.6) 4.2 (3.7–4.8) 0.18
Length, cm 51 (49.7–53.5) 53.9 (51–55.4) 0.21
Feeding characteristics #PO feeding experience, days 244 (168–497) 14 (8–32) 0.03
#to first PO feed, days 3 (2–15) 4 (0–5) 0.42
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Note: Data presented as median (IQR).

3.2 |. Pharyngeal contractile and regulatory characteristics

Analytical variables as explained in Figure 1 were compared for differences in preterm and full-term-born infants (Figure 2). Distributions of UES nadir pressures showed no significant difference between the groups (Figure 2A). Although preterm infants had significantly higher PhCI (P = 0.01) for each pharyngeal swallow (Figure 2B), they had lower pharyngeal contraction frequency (P = 0.02; Figure 2C) and decreased pharyngeal activity of 29% ± 4% vs 42% ± 4% for full-term infants (P = 0.03). Activity-to-quiescence ratio was 0.5 ± 0.2 for preterm infants vs 1 ± 0.2 for full-term infants (P = 0.03). Note that the preterm infants have a significantly lesser number of contractions within burst: 2.19 ± 0.36 vs 3.36 ± 0.04 for full-term infants (P = 0.04, Figure 2D), despite not showing a significant difference in the number of bursts: 8.2 ± 1.4 bursts vs 9.2 ± 1.6 bursts for full-term infants (P = 0.66) or in the duration of bursts: 2.01 ± 0.4 seconds for preterm vs 3.20 ± 0.5 seconds for full-term (P = 0.06) which may be a marker of regulatory efficiency. This was also supported by the burst activity results: 23 ± 4 in the preterm-born vs 37% ± 5% in full-term born (P = 0.05).

FIGURE 2.

FIGURE 2

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Upper esophageal sphincter (UES) and Pharyngeal activity characteristics of full-term-born and preterm-born infants: Boxplots in (A) show a comparison of distribution of UES nadir pressures, (B) show comparisons in the distributions of pharyngeal contractile characteristics, while those in (C) and (D) show comparisons in the distribution of regulatory characteristics. The black dotted line represents means of the distributions, and the solid black lines within the boxes represent the median

3.3 |. Effects of GA, pharyngeal activity, and UES relaxation on PhCI

For both bivariate and full model statistical analyses, preterm birth, PMA, pharyngeal contraction frequency, number of pharyngeal bursts, and UES nadir pressure had a significant effect on PhCI (Table 2). Note the effect of positive UES nadir pressure on PhCI.

TABLE 2.

Regression analysis summary

Dependent characteristic Independent characteristics Bivariate analysis (β ± SE) Full model (β ± SE)
PhCI, mm Hg cm s Preterm 27.7 ± 14.0* 33.1 ± 13.0*
PMA, weeks 7.6 ± 3.0* 7.1 ± 2.9*
Frequency, Hz −5.8 ± 1.3** −6.4 ± 1.3**
Number of bursts, # −2.3 ± 1.0* −2.1 ± 1.0*
UES nadir pressure, mm Hg 0.4 ± 0.1* 0.4 ± 0.1**
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Note: Bivariate analysis used for selecting variables to construct the full model as well as the coefficient values from the full model. Bivariate analysis results show the exclusive relationship between each independent characteristic and PhCI. As all characteristics tested here showed a significant relationship with PhCI, all of them were used to construct the full model. PhCI is higher for preterm births and increases with PMA and UES nadir pressure but decreases when there is in an increase in number of bursts and pharyngeal contraction frequency.

*

P < 0.05,

**

P < 0.001.

4 |. DISCUSSION

During normal pregnancy, swallowing functions develop through continued swallowing experiences of amniotic fluid in utero until full-term birth, such that the neonate is capable of self-regulation of aerodigestive functions during oral feeding. On the other hand, in the preterm-born infant, such skills are delayed and evolve with post-natal maturation. The characteristics of pharyngeal contractility and regulation during swallowing in preterm compared with full-term-born infants are not well understood. This study was undertaken to examine the pharyngeal and UES activity characteristics of preterm and full-term-born infants so as to identify how differences in intrauterine and extrauterine maturation affect the functions of pharynx. Specifically, we tested the hypothesis that preterm infants are distinct from full-term-born infants in pharyngeal function (contractility and regulation) at identical postnatal maturation, and examined if this translates to their nutritive milk intake efficiency.

Significantly, (a) despite more oral feeding experiences preterm infants (compared to full-term-born at identical full-term PMA) consumed less milk and had fewer pharyngeal contractions but higher PhCI per individual contraction; (b) preterm birth, longer postnatal maturation and higher UES nadir pressures result in higher PhCI while greater pharyngeal contraction frequencies and number of bursts lead to a lower PhCI; (c) in full-term-born infants vs preterm-born infants, overall pharyngeal activity was greater by 1.5-fold, activity-to-quiescence ratio was greater by 2-fold along with an increase in contractions within the burst. This is the first study to apply the 3-dimensional swallowing and regulatory metrics in the neonatal setting. Collectively, these findings suggest that the regulatory and contractile characteristics in preterm-born and full-term-born infants vary, thus suggesting differential development during postnatal maturation. Further studies are needed to examine the influence of environmental (process and practices) factors, experiential factors, and quality of oral nutritive swallowing experiences.

We noted that the preterm infants exert more pharyngeal contractile effort to swallow and may be prone to fatigue, as evidenced by the higher PhCI to start with, which is followed by prolonged quiescence. This may suggest that preterm infants initiate eating due to hunger but have limited endurance while maintaining coordination of airway protection with pharyngo-esophageal peristalsis for physiological stability. High-resolution manometry permits objective and reproducible examination of physiology using 3-dimensional contractile and relaxation integrals which can be used to examine effects of longitudinal maturation in health or disease and specific oral feeding therapies. The latter may include variation in feeding methods, such as bottle or breastfeeding.

In our study, we noted gestational and postnatal maturational differences in preterm and full-term-born infants (Figure 2). Our findings are in agreement with studies by Ballester et al, in that, among maturational piglet model for swallowing physiology, it was found that timing of swallowing and respiratory coordination changes with maturation.23 These effects were modified in piglets with peripheral neuropathology mediated by IX and X cranial nerves. Prior to our evaluation, preterm infants had more oral feeding experiences ex-utero at identical PMA. However, we note that preterm infants exerted greater effort than full-term infants but consumed less than half the volume. These findings suggest that there are several factors during extrauterine maturation in the neonatal ICU that might impede maturation of safe and efficient swallowing contractile and regulatory skills. Such factors may underlie in evaluation of consistent feeding readiness or feeding quality assessment; both of these are highly subjective and vary among providers. Variation between bottle and breastfeeding may be a factor, as well as presence of any neurological or pulmonary co-morbidities. Prospective, well-designed studies are needed to examine these variations.

4.1 |. Clinical and research implications and future directions are as follows

(a) Crib-side instrumental assessment to understand the pathophysiological basis of eating and swallowing safety is needed to validate diagnostic markers or potential therapies that may be of promise. Lack of such approaches is a recipe for multidisciplinary provider variation and lack of agreement with feeding protocols. Our studies, as in this paper, lend support to safe, reliable, and reproducible testing among high-risk infants at crib side. (b) The PhCI is a valuable marker for the presence of pharyngeal swallowing impairment and can be a metric to measure longitudinal changes with time and with process optimization. Such processes may include bottle vs breastfeeding, cue-based vs time-scheduled feeding, and initiation with non-nutritive vs nutritive stimulation. This metric is relatively simple and easy to calculate. (c) PhCI can be influenced by upstream and downstream motility; notably, the resistance offered at the UES during swallowing triggered peristalsis. The presence of lower or negative UES nadir pressures is a sign of sphincteric relaxation permitting bolus admittance. However, measurement of UES relaxation characteristics can be associated with pressures in the positive range, and this may be due to intrabolus pressure from the nutritive stimulus, brevity of sphincteric relaxation, or the position of the infant. Systematic longitudinal studies examining the relationship between PhCI and UES kinetics are needed in neonates to understand the rapidity of the UES relaxation and postswallow UES contractile response. UES nadir pressures had a direct effect on PhCI in that the PhCI was greater when the nadir pressures were positive, and may be related to incomplete relaxation. Thus, the therapeutic targets could be methods to promote UES relaxation. Application of PhCI could be useful in the context of examining pharyngo-UES phase of swallowing abnormalities, such as may be seen cricopharyngeal achalasia. (d) Inclusion of impedance with HRM offers further refinement of evaluations during feeding while assessing objective pressure topography concurrent with bolus movement in these high-risk infants. Similar approaches have been possible in adults and older children.24–27

5 |. SUMMARY AND CONCLUSIONS

In summary, HRM applications have made it possible to study contractility of the neonatal pharynx and esophagus in greater detail during crib-side studies. Therefore, we have undertaken this study to compare and understand the differences in pharyngeal contractile and regulatory activity characteristics of preterm and full-term-born infants. Significantly, we found that preterm infants would not attain the same level of milk extraction rates or pharyngeal activity: Quiescence functions through postnatal maturation at full-term PMA, when compared to full-term-born infants. Despite more oral nutritive experiences, preterm infants had underdeveloped excitatory and inhibitory rhythmic activity. Cranial nerve IX and X effects on sensory-motor responses and feedback (excitation-inhibitory rhythm regulation) remain underdeveloped in preterm-born even at full-term status. We speculate that the relationship between PhCI and UES regulatory (contractile and relaxation states) activity may contribute to the observed differences in preterm-born and full-term-born infants. The effect of neonatal neurological and aerodigestive morbidities and testing the effect of feeding therapies on postnatal development need further studies.

Key Points.

  • Preterm-born infants have a greater risk of developing swallowing dysfunction and feeding difficulties. It is unclear how postnatal maturation modifies pharyngeal contractile rhythms during oral feeding.

  • Preterm infants had lower milk extraction rates and swallowing efficiency as evidenced by decreased frequency and increased magnitude of pharyngeal contractility.

  • Pharyngeal contractile regulation is underdeveloped in preterm-born infants despite postnatal maturation equivalent to full-term status. High-resolution manometry methods offer clarification of potential mechanisms in health and disease among neonates.

Funding information

This study was supported in part by National Institutes of Health Grant PO1 DK-068051 (Shaker, Lang, Jadcherla).

Abbreviations:

GA

gestational age

HRM

high-resolution manometry

PhCI

pharyngeal contractile integral

PMA

postmenstrual age

UES

upper esophageal sphincter

Footnotes

DISCLOSURE STATEMENT

The authors declare no conflicts of interest.

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