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Greater analgesic effects of sucrose in the neonate predict greater weight gain to age 18 months
Appetite 146 (2020) 104508
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Greater analgesic effects of sucrose in the neonate predict greater weight gain to age 18 months
T
Julie C. Lumenga,b,c,∗, Xing Lid, Yunyi Hea, Ashley Gearhardte, Julie Sturzaa, Niko A. Kacirotia,f, Ming Lid, Katharine Astag, Betsy Lozoffa,b a
Center for Human Growth and Development, University of Michigan, Ann Arbor, MI, USA Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA c Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA d Department of Pediatrics, Peking University First Hospital, Beijing, China e Department of Psychology, University of Michigan, Ann Arbor, MI, USA f Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA g University of Michigan Medical School, Ann Arbor, MI, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Neonate Obesity
Intraoral sucrose has analgesic effects in the newborn period. The hedonic and analgesic effects of sucrose overlap and hedonic response to sweet food is associated with adiposity. The potential association between the analgesic effects of intraoral sucrose in the newborn period and subsequent weight gain has not been examined. Healthy, term newborns received 25% intraoral sucrose or water prior to metabolic screen heel stick. Negative affect, quiet alert behavior, and sleepiness were coded during heel stick. Weight and length were measured and z-score (WLZ) calculated at birth, 9, and 18 months. Mixed models tested associations of behavioral response to heel stick with WLZ trajectory among infants receiving sucrose (n = 154) versus water (n = 117). Among infants receiving sucrose prior to heel stick with birth WLZ ≥ the median, less negative affect and more sleepiness during heel stick were each associated with greater increases in WLZ. These associations were not present among infants receiving water only prior to heel stick. Greater analgesic effects of sucrose in the neonate were associated with greater future increases in WLZ, especially among infants with higher birth WLZ. Greater opioidmediated newborn behavioral response to intraoral sucrose may be a marker for future obesity risk. Clinical trials number: NCT02728141.
1. Introduction Intraoral sucrose activates the opioid system, which contributes to overlapping hedonic and analgesic behavioral effects observable from birth (Barr et al., 1994; Barr, Young, Wright, Gravel, & Alkawaf, 1999; Birch, 1999; E.; Blass, Fitzgerald, & Kehoe, 1987; E. M. Blass & Hoffmeyer, 1991; Hatfield, Gusic, Dyer, & Polomano, 2008; Herschel, Khoshnood, Ellman, Maydew, & Mittendorf, 1998; Mennella, Forestell, Morgan, & Beauchamp, 2009; Pepino & Mennella, 2005; Rada, Avena, & Hoebel, 2005; Stevens, Yamada, Ohlsson, Haliburton, & Shorkey, 2016; Taddio et al., 2010). Individual differences in the hedonic and analgesic effects of sucrose may have health relevance. Breastmilk (Ronald G Barr et al., 1999a; Bueno et al., 2013; Gray, Miller, Philipp, & Blass, 2002)and sweet foods are both analgesic (Mercer & Holder, 1997), indicating that the opioid effects of intraoral sucrose extend to
sweet foods. Greater hedonic response to sweet taste is associated with greater dietary intake of sweet foods (Berthoud, 2006; Birch & Fisher, 1998; de Wit & Phillips, 2012; Drewnowski, 2009)and greater adiposity in children (Asta et al., 2016; Ayres et al., 2012)and adults (Salbe, DelParigi, Pratley, Drewnowski, & Tataranni, 2004). To our knowledge, no studies have examined whether individual differences in the analgesic behavioral effects of sucrose in the newborn period predict future rate of weight gain. Given that rapid weight gain in infancy predicts future obesity risk (Monteiro & Victora, 2005), if the analgesic effect of sucrose is a behavioral marker of future obesity risk identifiable in the first 24 h after birth, this finding would have important theoretical and practical implications. If greater analgesic response to sucrose in the newborn period predicts greater future obesity risk, this finding would provide the foundation for a conceptual model in which a greater opioid response to
∗ Corresponding author. Center for Human Growth and Development 300 North Ingalls Street, 10th Floor, University of Michigan, Ann Arbor, MI, 48109-5406, USA. E-mail address: [email protected] (J.C. Lumeng).
https://doi.org/10.1016/j.appet.2019.104508 Received 1 July 2019; Received in revised form 31 October 2019; Accepted 31 October 2019 Available online 04 November 2019 0195-6663/ © 2019 Elsevier Ltd. All rights reserved.
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to hospital discharge and about 1 h after the last feeding. The goal was for infants not to be hungry and to be in a quiet and alert state at the start of the protocol. The entire protocol was videotaped. At protocol initiation, a research assistant, blind to the solution, administered 2 mL of 25% sucrose solution (Taddio et al., 2010) or sterile water by syringe into the side of the infant's mouth. At the end of a 2-min waiting period, a nurse performed the heel stick procedure, which began with a prick to the heel to draw blood, followed by gently massaging and squeezing the heel to extract enough blood for the newborn screening test, and concluding with application of a bandage. The heel stick procedure therefore consisted of the time from the initial prick to completion of the bandage application (mean time = 138.8 s, SD 80.4 s, range 32.7–560.1 s). Infant behavioral state was coded from videotape using Interact 9.0 software during the heel stick procedure. Videos were coded by two undergraduate students of Chinese origin. Both coders were blind to iron status of the infants and solutions given before heel stick and trained to reliability to a single reference coder (correlation ≥ 0.90 for duration of each behavioral state). Behavioral state was coded as duration, and behavioral states were mutually exclusive. Behavioral state codes were defined based on prior approaches (Bueno et al., 2013; Ekman & Friesen, 1978; Lawrence et al., 1993): (1) Negative Affect: crying (exhibiting negative vocalization, restlessness, thrashing, loud screaming, or a silent cry with grimace, tight facial muscles, and furrowed brow, chin, or jaw, sometimes accompanied by breath holding or facial color change), fussy (negative vocalization and the infant was restless and thrashing); or quiet negative (no vocalization, tight facial muscles, and a furrowed brow, chin, and jaw, excluding breath holding during infant screaming); (2) Quiet alert: awake, quiet, and peaceful; (3) Sleepy: eyes were closed and minimal body movement; (4) Uncodeable: Infant's face not visible on the camera. Uncodeable represented less than one percent of the observation time and these data are not presented. The percent of time spent in each behavioral state was calculated. Of 424 infants, 29 were excluded because they were crying prior to protocol initiation, and six were excluded due to video malfunction. Thus, 389 infants were randomized: 203 to sucrose and 186 to water. There were no significant differences in participant characteristics by randomization group.
sucrose in the newborn period, as reflected in greater hedonic and analgesic effects of sucrose, predicts greater dietary preference and intake of sweet foods, which in turn predict more rapid weight gain. If this conceptual model is accurate, behavioral response to sucrose in the newborn period could serve as a marker for obesity risk and an important mechanistic target for intervention. From a clinical perspective, there is a need to identify infants at risk for rapid weight gain before the weight gain occurs, which would allow greater monitoring and preventive interventions for infants at risk. Intraoral sucrose administration during the metabolic screen newborn heel stick is a common approach to providing analgesia. If behavioral response to this common pediatric procedure could be employed as a clinical marker for future obesity risk, preventive interventions could be provided to the infants most at risk. Therefore, this study sought to examine the associations between the analgesic response to sucrose and trajectories of infant weight-forlength from birth to age 18 months. We hypothesized that infants with a more robust analgesic effect of sucrose would experience more rapid weight gain. To test whether the observed associations were due specifically to analgesic response to sucrose, as opposed to the behavioral response to the heel stick, we repeated the analyses with infants who received a heel stick without sucrose. If the patterns of results were the same for infant behavioral response to heel stick whether the infant received sucrose or not, this would suggest that infant behavioral response to a painful stimulus, and not analgesic effects of sucrose, underlies associations with prospective trajectories of weight-for-length. If, however, the observed associations were present only among infants who received sucrose with the heel stick, and not among those who did not, this would suggest that individual differences in analgesia conferred by sucrose may have a mechanistic role in prospective trajectories of weight-for-length in infancy. 2. Methods 2.1. Overall study design and setting This was a secondary analysis of a subset of participants in a larger study (a randomized controlled trial [RCT] of infancy iron supplementation connected to an RCT of pregnancy iron supplementation to examine developmental effects of reducing iron deficiency in the fetus and young infant). The parent studies have been described in detail elsewhere (Lozoff et al., 2016; Zhao et al., 2015). The studies, conducted in rural Hebei Province, China, were approved by the ethics committees of the University of Michigan and Peking University First Hospital. Mothers were informed of the infant development study at prenatal visits. After delivery, project staff obtained signed informed consent. A total of 1482 infants from uncomplicated singleton pregnancies were enrolled between December 2009 and June 2012. Eligibility criteria for the sucrose substudy described here were that the infant was a healthy, term (≥37 weeks) infant without perinatal complications. The sample of neonates participating in the sucrose substudy were all recruited at one of the three study hospitals and were randomly selected with an oversampling of the infants who did not receive iron during pregnancy or infancy. Child sex and birth date were collected from the medical chart. Mothers reported household size, place of residence, education, and whether the infant was breastfed or not at 9 months. The randomly selected sucrose substudy sample did not differ from those not selected in terms of child sex, family size, gestational age, any breastfeeding vs. not at 9 months, birth weight, weight-for-length z-score (WLZ) at birth, 9 months or 18 months.
2.3. Anthropometry Infant weight and length were measured by trained research staff in the neonatal period and at 9 and 18 months during study visits. Weightfor-length z-score (WLZ) was calculated based on the World Health Organization (WHO) growth charts (Kuczmarski, 2002). The sample of infants with WLZ at age 18 months compared to those with WLZ only at birth and/or 9 months did not differ with regard to gestational age, birth WLZ, family size, place of residence, or maternal education. There were differences in child sex, with 46.3% male in the group with WLZ at 18 months, and 63.6% male in the group missing WLZ at 18 months (p = .0015). 2.4. Statistical analysis Analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC). Univariate statistics were used to describe the sample. All models controlled for the iron supplementation status of the mother-infant pair to account for the original study design. Analyses controlled for both pre- and post-natal supplementation. All models also controlled for birth weight-for-length z-score, whether the infant was breastfed vs. not at 9 months, and duration of the heel stick procedure. The sample was limited to infants who had measured birth WLZ, had at least one subsequent WLZ value, and had feeding method at 9 months. For the infants who received sucrose prior to heel stick, this provided a final samples size of n = 154. The sucrose sample with
2.2. Sucrose protocol Infants were randomly assigned 1:1 based on the last digit of their study identification number to receive sucrose or sterile water during the standard metabolic screen newborn heel stick, which occurred prior 2
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future WLZ among infants with birth WLZ at or above the median are shown in Figs. 1 and 2. Among infants with birth WLZ at or above the median, less negative affect (β = −2.31 [95% CI -3.56 to −1.06], p < .01) and greater sleepiness (β = 1.64 [(95% CI 0.41–2.87)], p < .01) were each associated with higher WLZ trajectories during infancy. In addition, the effect of negative affect on WLZ increases with age, as indicated by a significant estimate for interaction term of age with negative affect (β = −0.14, p < .05). Fig. 1 shows that for infants with lower negative affect (below the median) the WLZ curve is higher vs. infants with higher negative affect (at or above the median), and the difference in WLZ between the two curves increases with age, from 0.2 at birth to over 0.6 at 18 months. A reverse pattern is observed for the effect of sleepiness on WLZ (Fig. 2), where for infants with higher sleepiness (at or above the median) the WLZ curve is higher vs. infants with lower sleepiness (below the median), and while the difference on WLZ between two groups increases with age it is not significant. For infants below the median, there were no associations with behavioral response to sucrose with future WLZ.
complete data included in the analysis (n = 154) did not differ from the sample excluded (n = 49) with regard to child sex, family size, feeding method at 9 months, birth weight, or WLZ at birth or 9 months. The sample with complete data had a slightly higher gestational age compared to the sample without complete data (39.7 weeks vs. 39.3 weeks; p = .04) and a slightly lower WLZ at 18 months compared to the sample without complete data (0.62 vs. 0.99; p = .02). For the infants who received water prior to heel stick, this provided a final samples size of n = 117. The water sample with complete data included in the analysis (n = 117) did not differ from the sample excluded (n = 69) with regard to child sex, gestational age, family size, feeding method at 9 months, birth weight, WLZ at birth, 9 months or 18 months. To examine whether the behavioral response to sucrose predicted different growth patterns, we used mixed models controlled for prenatal and postnatal iron supplementation, birth weight-for-length zscore, and whether the infant was breastfed vs. not at 9 months, including age, the quadratic term for age (to account for the fact that change in WLZ is non-linear), behavioral response to sucrose, the interaction of behavioral response to sucrose with age (to account for the possibility that the effects of sucrose on WLZ may differ by age), and the interaction of the behavioral response to sucrose with the quadratic term for age (to account for the possibility that the effects of sucrose on WLZ may differ by age in a non-linear fashion). Since the interaction of the behavioral response to sucrose and the quadratic term for age was not significant in any of these models, this term was removed. Preliminary analyses showed significant differences in patterns of association based on birth WLZ and we therefore stratified the models by birth WLZ at or above versus below the median. Specifically, the interaction term of age by birth WLZ (high vs. low) was highly significant (p < .0001) and the interaction term of the quadratic term for age and birth WLZ (high vs. low) was highly significant (p < .01) in all growth pattern models with each behavioral response to sucrose. The interaction term of age by behavioral response by birth WLZ (high vs. low) was highly significant (p < .01) in some, although not all models. To examine whether the behavioral response to water predicted different growth patterns, we repeated the analyses described above in the sample of infants who received water prior to heel stick. Finally, we also repeated the analyses described above, including both the water and sucrose samples simultaneously in the analyses, and then tested the main effect of “condition” (sucrose vs. water) and interaction of condition with each behavioral response to solution.
3.2. Associations between behavioral response to heel stick and future WLZ among infants who received water (and not sucrose) prior to heel stick Table 3 shows the change in WLZ from birth to 18 months, as predicted by age and behavioral response to heel stick in the perinatal period following the delivery of water (and not sucrose), stratified by birth WLZ below the median compared to at or above the median. As in the sucrose group, WLZ increased with age among infants with birth WLZ below the median. As expected, and similar to the sucrose group, infants with birth WLZ below the median showed more rapid increase in WLZ initially that then tapered off with age, as reflected in the significant quadratic terms for age. Unlike in the sucrose group, we did not find significant associations between behavioral response to water and future WLZ in infants with a birth WLZ at or above the median. There was an unexpected association between behavioral response to water and future WLZ among infants with a birth WLZ below the median, however, the interaction term for quiet alert response to solution and solution type (sucrose vs. water) in predicting future WLZ was not significant (see Table 4). We tested the robustness of these findings by rerunning the models in the combined sample of infants who received either sucrose or water prior to heel stick, and testing the interaction of solution type (sucrose vs. water), with behavioral response to heel stick. As shown in Table 4, among the 141 infants with a birth WLZ at or above the median, the association of negative affect and being sleepy following heel stick with future WLZ differed significantly between infants who received sucrose vs. those who received water prior to heel stick. Specifically, negative affect and being sleepy as behavioral responses to heel stick preceded by sucrose predicted future WLZ, while negative affect and being sleepy as behavioral responses to heel stick preceded by water did not. We considered that differential attrition over time could have affected our results. We therefore reran the models predicting WLZ from birth to 18 months including only those infants with complete data for WLZ at birth, 9 months, and 18 months and found no significant differences in the pattern of results.
3. Results Characteristics of the sample are shown in Table 1. The sample was about half male with a mean gestational age of 39.7 (SD 1.1) weeks and mean birthweight of 3.3 (SD 0.4) kilograms. As expected, sucrose was more effective than water in reducing negative affect [81.5% (SD 16.0%) vs 86.8% (SD 12.6%), p = .003] and increasing quiet alert behavior [5.2% (SD 10.2%) vs. 2.1% (SD 5.4%), p = .001] following the heel stick. 3.1. Associations between behavioral response to heel stick and future WLZ among infants who received sucrose prior to heel stick
4. Discussion
Table 2 shows the change in WLZ from birth to 18 months, as predicted by age and behavioral response to heel stick in the perinatal period following the delivery of sucrose, stratified by birth WLZ below the median compared to at or above the median. WLZ increased with age among infants with birth WLZ below the median. As expected, infants with birth WLZ below the median as well as those at or above the median showed more rapid increase in WLZ initially that then tapered off with age, as reflected in the significant quadratic terms for age. Overall, we found that the association between behavioral response to sucrose and future WLZ was most robust among infants with higher birth WLZ. The associations of negative affect and sleepiness with
This study found that a greater analgesic effect of sucrose in the newborn period was associated with greater increases in WLZ, particularly among infants with higher birth WLZ. The observation that behavioral response to heel stick preceded by water (and not sucrose) was not associated with future WLZ supports the conceptual model that analgesic effects of sucrose are mechanistically related to future WLZ in infancy. We did not find support for the alternative hypothesis that general behavioral response to heel stick, independent of sucrose analgesic effects, predicts future WLZ. In addition, these results were 3
Sex (n, %) Female Male Family members in household (n, SD) Place of residence (n, %) Urban Rural Maternal education ≥ high school (n, %) Gestational age (weeks, mean, SD) Birthweight (kg, mean, SD) Birthweight z-score (mean, SD) Any breastfeeding at 9 months (n, %) Yes No Duration of heel stick procedure (seconds, mean, SD) WLZ (mean, SD) Birth 9 months 18 months Δ WLZ (mean, SD) Birth to 9 mos Birth to 18 mos 9 mos–18 mos Behavioral response (% time, mean, SD) Negative affect Quiet alert Sleepy
Characteristic
80 (52.0%) 74 (48.0%) 3.8 (1.3)
40 (26.3%) 112 (73.7%) 50 (32.7%) 39.7 (1.0) 3.3 (0.4) −0.4 (0.8)
137 (89.0%) 17 (11.0%) 137.8 (83.9)
0.2 (1.1) 1.0 (1.2) 0.6 (1.0) 0.8 (1.4) 0.4 (1.4) −0.4 (0.8)
81.5 (16.0) 5.2 (10.2) 13.2 (13.6)
65 (24.5%) 200 (75.5%) 88 (32.8%)
39.7 (1.1)
3.3 (0.4) −0.3 (0.8)
233 (86.0%) 38 (14.0%) 136.7 (79.6)
0.2 (1.0) 1.0 (1.1) 0.7 (1.0)
0.8 (1.3) 0.4 (1.3) −0.3 (0.8)
83.8 (14.8) 3.9 (8.6) 12.3 (13.0)
N = 154
N = 271
134 (49.4%) 137 (50.6%) 3.8 (1.2)
Sample receiving sucrose prior to heel stick
Total analytic sample
Table 1 Characteristics of infants in the analytic sample.
4 86.8 (12.6) 2.1 (5.4) 11.0 (12.2)
0.7 (1.2) 0.5 (1.2) −0.2 (0.8)
0.2 (1.0) 0.9 (1.1) 0.7 (1.0)
96 (82.0%) 21 (18.0%) 135.2 (73.7)
3.4 (0.3) −0.2 (0.8)
39.7 (1.1)
25 (22.1%) 88 (77.9%) 38 (33.0%)
54 (46.2%) 63 (53.8%) 3.8 (1.1)
N = 117
Sample receiving water prior to heel stick
N (%) or mean (SD)
.003 .001 .19
.64 .78 .12
.93 .56 .45
.79
.17 .15 .10
.69
.95
.43
.73
.34
p-value (sucrose vs. water)
82.5 (11.0) 2.8 (6.3) 14.5 (11.8)
0.2 (1.2) −0.4 (1.2) −0.4 (0.7)
1.0 (0.8) 1.2 (1.2) 0.7 (1.0)
65 (85.5%) 11 (14.5%) 134.0 (79.2)
3.5 (0.4) 0.0 (0.8)
39.7 (0.9)
18 (24.0%) 57 (76.0%) 21 (28.0%)
34 (44.7%) 42 (55.3%) 3.9 (1.4)
N = 76
80.6 (19.6) 7.5 (12.6) 11.8 (15.0)
88.8 (11.6) 1.0 (3.5) 10.1 (11.5)
0.2 (1.1) 0.0 (0.9) −0.2 (0.8)
0.8 (0.5) 1.1 (1.1) 0.9 (0.9)
−0.6 (0.6) 0.8 (1.2) 0.6 (1.0) 1.5 (1.2) 1.2 (1.2) −0.4 (0.9)
53 (81.5%) 12 (18.5%) 139.3 (78.1)
3.5 (0.2) 0.1 (0.6)
39.9 (1.1)
13 (20.3%) 51 (79.7%) 23 (36.5%)
31 (47.7%) 34 (52.3%) 3.9 (1.1)
N = 65
72 (92.3%) 6 (7.7%) 141.6 (88.6)
3.1 (0.3) −0.7 (0.6)
39.7 (1.1)
22 (28.6%) 55 (71.4%) 29 (37.2%)
46 (59.0%) 32 (41.0%) 3.7 (1.3)
N = 78
83.9 (13.7) 3.6 (6.9) 12.4 (13.3)
1.4 (1.1) 1.2 (1.3) −0.1 (0.9)
−0.7 (0.7) 0.7 (1.1) 0.5 (1.2)
41 (82.0%) 9 (18.0%) 129.5 (68.8)
3.2 (0.3) −0.6 (0.8)
39.5 (1.2)
12 (25.0%) 36 (75.0%) 14 (28.0%)
22 (44.0%) 28 (56.0%) 3.6 (1.0)
N = 50
birth WLZ < median
birth WLZ ≥ median
birth WLZ ≥ median
birth WLZ < median
Sample receiving water prior to heel stick
Sample receiving sucrose prior to heel stick
.008 < .0001 .24
< .0001 < .0001 .45
< .0001 .08 .27
.84
< .0001 < .0001 .23
.32
.50
.73
.32
.24
p-value (birth WLZ ≥ vs. < median x condition (sucrose vs. water)
J.C. Lumeng, et al.
Appetite 146 (2020) 104508
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Table 2 Association of behavioral response to sucrose with WLZ from birth to 18 months stratified by birth WLZ (n = 154). Birth WLZ below the median (n = 78)a Age Negative affect 5.92 (0.78)*** Quiet alert 5.60 (0.87)*** Sleepy 5.86 (0.76)*** Birth WLZ at or above the median (n = 76)a Negative affect −1.47 (0.73)* Quiet alert −1.25 (0.74) Sleepy −1.33 (0.76)
Age x age
Behavioral response
Age x behavioral response
−1.00 (0.15)*** −1.00 (0.15)*** −1.00 (0.15)***
−0.16 (0.36) 0.16 (0.57) 0.16 (0.46)
0.06 (0.04) 0.00 (0.06) −0.10 (0.05)
−0.33 (0.13)* −0.32 (0.13)* −0.31 (0.13)*
−2.31 (0.64)** 1.51 (1.22) 1.64 (0.63)*
−0.14 (0.06)* 0.17 (0.11) 0.08 (0.06)
*p < .05; **p < .01; ***p < .001. a All models controlled for prenatal and postnatal iron supplementation, birth weight-for-length z-score, whether the infant was breastfed vs. not at 9 months, and duration of the heel stick procedure; age centered at mean of 9 months to reduce multicollinearity between linear and quadratic term; behavioral responses centered at median value for that response. Dependent variable is WLZ*100. Values are fixed effect beta estimate (standard error).
Fig. 1. WLZ trajectory among infants with higher birth WLZ, stratified by higher vs. lower negative affect during newborn heel stick following sucrose administration.
Fig. 2. WLZ trajectory among infants with higher birth WLZ, stratified by higher vs. lower sleepiness during newborn heel stick following sucrose administration.
5
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Table 3 Association of behavioral response to water with WLZ from birth to 18 months stratified by birth WLZ (n = 117). Birth WLZ below the median (n = 50)a Age Negative affect 4.84 (1.03)*** Quiet alert 4.42 (1.10)*** Sleepy 4.97 (1.07)*** Birth WLZ at or above the median (n = 65)a Negative affect 0.84 (0.85) Quiet alert 1.12 (0.87) Sleepy 0.81 (0.83)
Age x age
Behavioral response
Age x behavioral response
−0.81 (0.19)*** −0.81 (0.19)*** −0.82 (0.20)***
−1.42 (0.80) 3.28 (1.44)* 0.38 (0.80)
−0.18 (0.09) 0.30 (0.15) 0.07 (0.09)
−0.30 (0.17) −0.30 (0.17) −0.30 (0.17)
0.66 (0.74) −2.93 (2.15) −0.34 (0.74)
0.00 (0.07) −0.27 (0.23) 0.02 (0.07)
*p < .05; **p < .01; ***p < .001. a All models controlled for prenatal and postnatal iron supplementation, birth weight-for-length z-score, whether the infant was breastfed vs. not at 9 months, and duration of the heel stick procedure; age centered at mean of 9 months to reduce multicollinearity between linear and quadratic term; behavioral responses centered at median value for that response. Dependent variable is WLZ*100. Values are fixed effect beta estimate (standard error).
disease hypothesis posits that fetal programming prenatally, such as through epigenetic changes, alters obesity risk (Gillman, 2005). Infant birthweight is one marker of the intrauterine environment. Birthweight or weight-for-length at birth as a marker of adiposity may be associated with neonatal behavioral response to sucrose or may moderate links between behavioral response to sucrose and rate of weight gain. The intrauterine environment is a powerful mediator of obesity risk and a contributor to birthweight (Oken & Gillman, 2003). As others have hypothesized (Portella & Silveira, 2014), it is possible that substances produced by the placenta or epigenetic changes (Gillman & Ludwig, 2013) may promote neurobiological changes in the infant brain linking sweet taste to drive to eat. Just as there is individual variability in the soothing effects of comfort foods in adults (Dallman et al., 2003), it is possible that certain infants, especially those of greater birth weight, are programmed, whether genetically, epigenetically, or from exposure in utero, to have greater opioid response to sweet foods in early life. In one study, greater birth weight was associated with more robust hedonic response to sweet taste in the newborn period (Ayres et al., 2012). In infants exposed to gestational diabetes, and thus more likely to be of a greater birth weight, increased soothability in infancy was associated with later early childhood obesity (Faith et al., 2019) and using food to soothe has been linked to infant weight gain (Stifter & Moding, 2015). Perhaps infants with programmed greater reward response to sweet taste respond robustly to food when stressed and thus their parents use food to soothe more often due to the learned effectiveness. Our data support that the individual variability in the analgesic effects of sucrose and links to subsequent weight gain may be modified by birth weight, but these questions warrant additional investigation. There are also important developmental effects to consider. The analgesic effect of sucrose seems to decline developmentally, being most potent in the newborn period, at least in rats (Anseloni et al.,
independent of the infant's birth weight-for-length z-score, whether or not the infant was breastfed, and the duration of the heel stick procedure. Overall, our findings are consistent with the hypothesized conceptual model that a more robust opioid response to sucrose detectable in the newborn period confers future obesity risk, potentially mediated through hedonic response to sweet taste and greater dietary intake of sweet foods. Behavioral response to intraoral sucrose during the newborn heelstick may be an observable behavioral indicator of future obesity risk and therefore have clinical implications for delivering preventive interventions to subgroups of infants at risk. The rate of weight gain in the first year of life is a robust risk factor for obesity later in childhood and into adulthood, independent of prenatal factors or birth weight (Baird et al., 2005; Dennison, Edmunds, Stratton, & Pruzek, 2006; Ong & Loos, 2006; Taveras et al., 2011). Preventing rapid weight gain in infancy is an important target for obesity prevention. However, the mechanisms of rapid weight gain in the first year of life are unknown (Lumeng, Taveras, Birch, & Yanovski, 2015). Eating behavior is a likely contributor to differential rates of weight gain. Infants with a vigorous sucking pattern (Agras, Kraemer, Berkowitz, & Hammer, 1990; Agras, Kraemer, Berkowitz, Korner, & Hammer, 1987; Waterland, Berkowitz, Stunkard, & Stallings, 1998), and whose mothers rate them as having a “big appetite” (Llewellyn, van Jaarsveld, Johnson, Carnell, & Wardle, 2010) gain more weight in infancy. Our findings suggest that newborn analgesic response to intraoral sucrose may be an additional behavioral indicator of risk for rapid infant weight gain. We also found that the associations between the analgesic effects of sucrose and future weight gain were more robust among infants with higher birth WLZ. The mechanism underlying this finding are unclear. The intrauterine environment is associated with the offspring's obesity risk, though the mechanisms of effect are only beginning to be elucidated (Oken & Gillman, 2003). The developmental origins of health and
Table 4 Association of behavioral response to water or sucrose with WLZ from birth to 18 months stratified by birth WLZ (n = 269). Birth WLZ below the median (n = 128)a Age
Age x age
Negative affect 5.50 (0.63)*** −0.93 Quiet alert 5.24 (0.69)*** −0.93 Sleepy 5.58 (0.62)*** −0.93 Birth WLZ at or above the median (n = 141)a Negative affect −0.13 (0.54) −0.31 Quiet alert −0.11 (0.57) −0.31 Sleepy −0.22 (0.56) −0.31
Behavioral response
Age x behavioral response
Sucrose vs. water
Sucrose/water x behavioral response
(0.12)*** (0.12)*** (0.12)***
−0.68 (0.67) 2.24 (1.27)† 0.02 (0.69)
0.02 (0.03) 0.04 (0.05) −0.05 (0.04)
3.89 (11.56) 8.58 (12.65) 3.77 (11.52)
0.39 (0.75) −1.78 (1.38) 0.17 (0.81)
(0.11)** (0.11)** (0.11)**
0.55 (0.67) −2.98 (2.14) −0.32 (0.68)
−0.05 (0.04) 0.05 (0.10) 0.04 (0.04)
−9.98 (10.35) −9.26 (10.93) −11.33 (10.62)
−2.79 (0.87)** 4.38 (2.42)† 1.94 (0.87)*
†p < .10, *p < .05; **p < .01; ***p < .001. a All models controlled for prenatal and postnatal iron supplementation, birth weight-for-length z-score, whether the infant was breastfed vs. not at 9 months, and duration of heel stick procedure; age centered at mean of 9 months to reduce multicollinearity between linear and quadratic term; behavioral responses centered at median value for that response. Dependent variable is WLZ*100. Sucrose (=1), Water (0). Values are fixed effect beta estimate (standard error). 6
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2002). In addition, preference for sweet taste declines in adolescence (Desor & Beauchamp, 1987). While we found that the analgesic properties of sucrose were more robust among infants with higher WLZ, others have found that at school age, the analgesic properties of sucrose are weaker among overweight children (Pepino & Mennella, 2005). The analgesic properties of sucrose, and their association with appetitive drive and weight gain, may change developmentally. These questions require further study. Interpretation of these findings should note the study limitations. The longitudinal design is a strength, but attrition was high. There were missing data due to attrition, but our sensitivity analysis did not indicate that this attrition affected the results. Results may not be generalizable to other study populations outside infants born in China. It may be particularly worth examining whether these findings extend to other populations given that the weight-for-length z-scores of this cohort were, though still well within the normal range, above average compared to international references at 9 and 18 months. In addition, 7% of infants in the overall sample were excluded from the protocol because they were crying prior to protocol initiation. This group could represent infants who are particularly difficult to soothe and these findings may therefore not be generalizable to infants who are especially difficult to soothe. Tighter experimental control in the form of standardizing the duration of the painful stimulus would increase confidence in the study findings, but is not possible due to ethical concerns in extending the duration of the painful stimulus for experimental reasons only among healthy infants. Likewise, shortening the duration of the painful stimulus to achieve consistency across infants is also not possible since the primary purpose of the procedure was to obtain a blood sample, and the procedure could not be terminated early without a sufficient blood sample simply for the purposes of this study. In addition, a within-subjects design in which the same infants received sucrose versus water in two painful procedures would increase confidence in the findings, but is not ethically possibly given that healthy infants undergo only one painful heel stick. Despite these limitations, the study was able to describe prospective associations between the analgesic effects of sucrose at birth and future growth, which to our knowledge has not been previously described. In summary, a greater analgesic effect of sucrose in the newborn period was associated with greater rate of weight gain from birth to age 18 months. This effect was stronger among infants with higher birth WLZ. The opioid response to sweet taste may be an important driver of infant appetite and in turn, infant rate of weight gain. Individual differences in behavioral response to sweet taste detectable in infancy may contribute to obesity risk and may be a novel marker for those at risk and mechanistic intervention target for obesity prevention.
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Financial disclosure The authors have no financial relationships or conflicts of interest to disclose. Funding source National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development R01HD052069. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.appet.2019.104508. References Agras, W. S., Kraemer, H. C., Berkowitz, R. I., & Hammer, L. D. (1990). Influence of early feeding style on adiposity at 6 years of age. The Journal of Pediatrics, 116(5), 805–809. Agras, W. S., Kraemer, H. C., Berkowitz, R. I., Korner, A. F., & Hammer, L. D. (1987). Does
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Systematic Reviews(7). Stifter, C. A., & Moding, K. J. (2015). Understanding and measuring parent use of food to soothe infant and toddler distress: A longitudinal study from 6 to 18 months of age. Appetite, 95, 188–196. Taddio, A., Appleton, M., Bortolussi, R., Chambers, C., Dubey, V., Halperin, S., ... Shah, V. (2010). Reducing the pain of childhood vaccination: An evidence-based clinical practice guideline. Canadian Medical Association Journal, 182(18), E843–E855. https://doi.org/10.1503/cmaj.101720. Taveras, E. M., Rifas-Shiman, S. L., Sherry, B., Oken, E., Haines, J., Kleinman, K., ... Gillman, M. W. (2011). Crossing growth percentiles in infancy and risk of obesity in childhood. Archives of Pediatrics and Adolescent Medicine, 165(11), 993–998. Waterland, R. A., Berkowitz, R. I., Stunkard, A. J., & Stallings, V. A. (1998). Calibratedorifice nipples for measurement of infant nutritive sucking. The Journal of Pediatrics, 132(3), 523–526. https://doi.org/10.1016/s0022-3476(98)70033-2. de Wit, H., & Phillips, T. J. (2012). Do initial responses to drugs predict future use or abuse? Neuroscience & Biobehavioral Reviews, 36(6), 1565–1576. Zhao, G., Xu, G., Zhou, M., Jiang, Y., Richards, B., Clark, K. M., ... Tardif, T. (2015). Prenatal iron supplementation reduces maternal anemia, iron deficiency, and iron deficiency anemia in a randomized clinical trial in rural China, but iron deficiency remains widespread in mothers and neonates. Journal of Nutrition, 145(8), 1916–1923.
Clinical Nutrition, 90(3), 780S–788S. Mercer, M. E., & Holder, M. D. (1997). Antinociceptive effects of palatable sweet ingesta on human responsivity to pressure pain. Physiology & Behavior, 61(2), 311–318. Monteiro, P. O. A., & Victora, C. G. (2005). Rapid growth in infancy and childhood and obesity in later life–a systematic review. Obesity Reviews, 6(2), 143–154. Oken, E., & Gillman, M. W. (2003). Fetal origins of obesity. Obesity Research, 11(4), 496–506. https://doi.org/10.1038/oby.2003.69. Ong, K. K., & Loos, R. J. (2006). Rapid infancy weight gain and subsequent obesity: Systematic reviews and hopeful suggestions. Acta Paediatrica, 95(8), 904–908. Pepino, M. Y., & Mennella, J. A. (2005). Sucrose-induced analgesia is related to sweet preferences in children but not adults. Pain, 119(1–3), 210–218. Portella, A. K., & Silveira, P. P. (2014). Neurobehavioral determinants of nutritional security in fetal growth–restricted individuals. Annals of the New York Academy of Sciences, 1331(1), 15–33. https://doi.org/10.1111/nyas.12390. Rada, P., Avena, N., & Hoebel, B. (2005). Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience, 134(3), 737–744. Salbe, A. D., DelParigi, A., Pratley, R. E., Drewnowski, A., & Tataranni, P. A. (2004). Taste preferences and body weight changes in an obesity-prone population. American Journal of Clinical Nutrition, 79(3), 372–378. Stevens, B., Yamada, J., Ohlsson, A., Haliburton, S., & Shorkey, A. (2016). Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database of
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Greater analgesic effects of sucrose in the neonate predict greater weight gain to age 18 months
T
Julie C. Lumenga,b,c,∗, Xing Lid, Yunyi Hea, Ashley Gearhardte, Julie Sturzaa, Niko A. Kacirotia,f, Ming Lid, Katharine Astag, Betsy Lozoffa,b a
Center for Human Growth and Development, University of Michigan, Ann Arbor, MI, USA Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA c Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA d Department of Pediatrics, Peking University First Hospital, Beijing, China e Department of Psychology, University of Michigan, Ann Arbor, MI, USA f Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA g University of Michigan Medical School, Ann Arbor, MI, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Neonate Obesity
Intraoral sucrose has analgesic effects in the newborn period. The hedonic and analgesic effects of sucrose overlap and hedonic response to sweet food is associated with adiposity. The potential association between the analgesic effects of intraoral sucrose in the newborn period and subsequent weight gain has not been examined. Healthy, term newborns received 25% intraoral sucrose or water prior to metabolic screen heel stick. Negative affect, quiet alert behavior, and sleepiness were coded during heel stick. Weight and length were measured and z-score (WLZ) calculated at birth, 9, and 18 months. Mixed models tested associations of behavioral response to heel stick with WLZ trajectory among infants receiving sucrose (n = 154) versus water (n = 117). Among infants receiving sucrose prior to heel stick with birth WLZ ≥ the median, less negative affect and more sleepiness during heel stick were each associated with greater increases in WLZ. These associations were not present among infants receiving water only prior to heel stick. Greater analgesic effects of sucrose in the neonate were associated with greater future increases in WLZ, especially among infants with higher birth WLZ. Greater opioidmediated newborn behavioral response to intraoral sucrose may be a marker for future obesity risk. Clinical trials number: NCT02728141.
1. Introduction Intraoral sucrose activates the opioid system, which contributes to overlapping hedonic and analgesic behavioral effects observable from birth (Barr et al., 1994; Barr, Young, Wright, Gravel, & Alkawaf, 1999; Birch, 1999; E.; Blass, Fitzgerald, & Kehoe, 1987; E. M. Blass & Hoffmeyer, 1991; Hatfield, Gusic, Dyer, & Polomano, 2008; Herschel, Khoshnood, Ellman, Maydew, & Mittendorf, 1998; Mennella, Forestell, Morgan, & Beauchamp, 2009; Pepino & Mennella, 2005; Rada, Avena, & Hoebel, 2005; Stevens, Yamada, Ohlsson, Haliburton, & Shorkey, 2016; Taddio et al., 2010). Individual differences in the hedonic and analgesic effects of sucrose may have health relevance. Breastmilk (Ronald G Barr et al., 1999a; Bueno et al., 2013; Gray, Miller, Philipp, & Blass, 2002)and sweet foods are both analgesic (Mercer & Holder, 1997), indicating that the opioid effects of intraoral sucrose extend to
sweet foods. Greater hedonic response to sweet taste is associated with greater dietary intake of sweet foods (Berthoud, 2006; Birch & Fisher, 1998; de Wit & Phillips, 2012; Drewnowski, 2009)and greater adiposity in children (Asta et al., 2016; Ayres et al., 2012)and adults (Salbe, DelParigi, Pratley, Drewnowski, & Tataranni, 2004). To our knowledge, no studies have examined whether individual differences in the analgesic behavioral effects of sucrose in the newborn period predict future rate of weight gain. Given that rapid weight gain in infancy predicts future obesity risk (Monteiro & Victora, 2005), if the analgesic effect of sucrose is a behavioral marker of future obesity risk identifiable in the first 24 h after birth, this finding would have important theoretical and practical implications. If greater analgesic response to sucrose in the newborn period predicts greater future obesity risk, this finding would provide the foundation for a conceptual model in which a greater opioid response to
∗ Corresponding author. Center for Human Growth and Development 300 North Ingalls Street, 10th Floor, University of Michigan, Ann Arbor, MI, 48109-5406, USA. E-mail address: [email protected] (J.C. Lumeng).
https://doi.org/10.1016/j.appet.2019.104508 Received 1 July 2019; Received in revised form 31 October 2019; Accepted 31 October 2019 Available online 04 November 2019 0195-6663/ © 2019 Elsevier Ltd. All rights reserved.
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to hospital discharge and about 1 h after the last feeding. The goal was for infants not to be hungry and to be in a quiet and alert state at the start of the protocol. The entire protocol was videotaped. At protocol initiation, a research assistant, blind to the solution, administered 2 mL of 25% sucrose solution (Taddio et al., 2010) or sterile water by syringe into the side of the infant's mouth. At the end of a 2-min waiting period, a nurse performed the heel stick procedure, which began with a prick to the heel to draw blood, followed by gently massaging and squeezing the heel to extract enough blood for the newborn screening test, and concluding with application of a bandage. The heel stick procedure therefore consisted of the time from the initial prick to completion of the bandage application (mean time = 138.8 s, SD 80.4 s, range 32.7–560.1 s). Infant behavioral state was coded from videotape using Interact 9.0 software during the heel stick procedure. Videos were coded by two undergraduate students of Chinese origin. Both coders were blind to iron status of the infants and solutions given before heel stick and trained to reliability to a single reference coder (correlation ≥ 0.90 for duration of each behavioral state). Behavioral state was coded as duration, and behavioral states were mutually exclusive. Behavioral state codes were defined based on prior approaches (Bueno et al., 2013; Ekman & Friesen, 1978; Lawrence et al., 1993): (1) Negative Affect: crying (exhibiting negative vocalization, restlessness, thrashing, loud screaming, or a silent cry with grimace, tight facial muscles, and furrowed brow, chin, or jaw, sometimes accompanied by breath holding or facial color change), fussy (negative vocalization and the infant was restless and thrashing); or quiet negative (no vocalization, tight facial muscles, and a furrowed brow, chin, and jaw, excluding breath holding during infant screaming); (2) Quiet alert: awake, quiet, and peaceful; (3) Sleepy: eyes were closed and minimal body movement; (4) Uncodeable: Infant's face not visible on the camera. Uncodeable represented less than one percent of the observation time and these data are not presented. The percent of time spent in each behavioral state was calculated. Of 424 infants, 29 were excluded because they were crying prior to protocol initiation, and six were excluded due to video malfunction. Thus, 389 infants were randomized: 203 to sucrose and 186 to water. There were no significant differences in participant characteristics by randomization group.
sucrose in the newborn period, as reflected in greater hedonic and analgesic effects of sucrose, predicts greater dietary preference and intake of sweet foods, which in turn predict more rapid weight gain. If this conceptual model is accurate, behavioral response to sucrose in the newborn period could serve as a marker for obesity risk and an important mechanistic target for intervention. From a clinical perspective, there is a need to identify infants at risk for rapid weight gain before the weight gain occurs, which would allow greater monitoring and preventive interventions for infants at risk. Intraoral sucrose administration during the metabolic screen newborn heel stick is a common approach to providing analgesia. If behavioral response to this common pediatric procedure could be employed as a clinical marker for future obesity risk, preventive interventions could be provided to the infants most at risk. Therefore, this study sought to examine the associations between the analgesic response to sucrose and trajectories of infant weight-forlength from birth to age 18 months. We hypothesized that infants with a more robust analgesic effect of sucrose would experience more rapid weight gain. To test whether the observed associations were due specifically to analgesic response to sucrose, as opposed to the behavioral response to the heel stick, we repeated the analyses with infants who received a heel stick without sucrose. If the patterns of results were the same for infant behavioral response to heel stick whether the infant received sucrose or not, this would suggest that infant behavioral response to a painful stimulus, and not analgesic effects of sucrose, underlies associations with prospective trajectories of weight-for-length. If, however, the observed associations were present only among infants who received sucrose with the heel stick, and not among those who did not, this would suggest that individual differences in analgesia conferred by sucrose may have a mechanistic role in prospective trajectories of weight-for-length in infancy. 2. Methods 2.1. Overall study design and setting This was a secondary analysis of a subset of participants in a larger study (a randomized controlled trial [RCT] of infancy iron supplementation connected to an RCT of pregnancy iron supplementation to examine developmental effects of reducing iron deficiency in the fetus and young infant). The parent studies have been described in detail elsewhere (Lozoff et al., 2016; Zhao et al., 2015). The studies, conducted in rural Hebei Province, China, were approved by the ethics committees of the University of Michigan and Peking University First Hospital. Mothers were informed of the infant development study at prenatal visits. After delivery, project staff obtained signed informed consent. A total of 1482 infants from uncomplicated singleton pregnancies were enrolled between December 2009 and June 2012. Eligibility criteria for the sucrose substudy described here were that the infant was a healthy, term (≥37 weeks) infant without perinatal complications. The sample of neonates participating in the sucrose substudy were all recruited at one of the three study hospitals and were randomly selected with an oversampling of the infants who did not receive iron during pregnancy or infancy. Child sex and birth date were collected from the medical chart. Mothers reported household size, place of residence, education, and whether the infant was breastfed or not at 9 months. The randomly selected sucrose substudy sample did not differ from those not selected in terms of child sex, family size, gestational age, any breastfeeding vs. not at 9 months, birth weight, weight-for-length z-score (WLZ) at birth, 9 months or 18 months.
2.3. Anthropometry Infant weight and length were measured by trained research staff in the neonatal period and at 9 and 18 months during study visits. Weightfor-length z-score (WLZ) was calculated based on the World Health Organization (WHO) growth charts (Kuczmarski, 2002). The sample of infants with WLZ at age 18 months compared to those with WLZ only at birth and/or 9 months did not differ with regard to gestational age, birth WLZ, family size, place of residence, or maternal education. There were differences in child sex, with 46.3% male in the group with WLZ at 18 months, and 63.6% male in the group missing WLZ at 18 months (p = .0015). 2.4. Statistical analysis Analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC). Univariate statistics were used to describe the sample. All models controlled for the iron supplementation status of the mother-infant pair to account for the original study design. Analyses controlled for both pre- and post-natal supplementation. All models also controlled for birth weight-for-length z-score, whether the infant was breastfed vs. not at 9 months, and duration of the heel stick procedure. The sample was limited to infants who had measured birth WLZ, had at least one subsequent WLZ value, and had feeding method at 9 months. For the infants who received sucrose prior to heel stick, this provided a final samples size of n = 154. The sucrose sample with
2.2. Sucrose protocol Infants were randomly assigned 1:1 based on the last digit of their study identification number to receive sucrose or sterile water during the standard metabolic screen newborn heel stick, which occurred prior 2
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future WLZ among infants with birth WLZ at or above the median are shown in Figs. 1 and 2. Among infants with birth WLZ at or above the median, less negative affect (β = −2.31 [95% CI -3.56 to −1.06], p < .01) and greater sleepiness (β = 1.64 [(95% CI 0.41–2.87)], p < .01) were each associated with higher WLZ trajectories during infancy. In addition, the effect of negative affect on WLZ increases with age, as indicated by a significant estimate for interaction term of age with negative affect (β = −0.14, p < .05). Fig. 1 shows that for infants with lower negative affect (below the median) the WLZ curve is higher vs. infants with higher negative affect (at or above the median), and the difference in WLZ between the two curves increases with age, from 0.2 at birth to over 0.6 at 18 months. A reverse pattern is observed for the effect of sleepiness on WLZ (Fig. 2), where for infants with higher sleepiness (at or above the median) the WLZ curve is higher vs. infants with lower sleepiness (below the median), and while the difference on WLZ between two groups increases with age it is not significant. For infants below the median, there were no associations with behavioral response to sucrose with future WLZ.
complete data included in the analysis (n = 154) did not differ from the sample excluded (n = 49) with regard to child sex, family size, feeding method at 9 months, birth weight, or WLZ at birth or 9 months. The sample with complete data had a slightly higher gestational age compared to the sample without complete data (39.7 weeks vs. 39.3 weeks; p = .04) and a slightly lower WLZ at 18 months compared to the sample without complete data (0.62 vs. 0.99; p = .02). For the infants who received water prior to heel stick, this provided a final samples size of n = 117. The water sample with complete data included in the analysis (n = 117) did not differ from the sample excluded (n = 69) with regard to child sex, gestational age, family size, feeding method at 9 months, birth weight, WLZ at birth, 9 months or 18 months. To examine whether the behavioral response to sucrose predicted different growth patterns, we used mixed models controlled for prenatal and postnatal iron supplementation, birth weight-for-length zscore, and whether the infant was breastfed vs. not at 9 months, including age, the quadratic term for age (to account for the fact that change in WLZ is non-linear), behavioral response to sucrose, the interaction of behavioral response to sucrose with age (to account for the possibility that the effects of sucrose on WLZ may differ by age), and the interaction of the behavioral response to sucrose with the quadratic term for age (to account for the possibility that the effects of sucrose on WLZ may differ by age in a non-linear fashion). Since the interaction of the behavioral response to sucrose and the quadratic term for age was not significant in any of these models, this term was removed. Preliminary analyses showed significant differences in patterns of association based on birth WLZ and we therefore stratified the models by birth WLZ at or above versus below the median. Specifically, the interaction term of age by birth WLZ (high vs. low) was highly significant (p < .0001) and the interaction term of the quadratic term for age and birth WLZ (high vs. low) was highly significant (p < .01) in all growth pattern models with each behavioral response to sucrose. The interaction term of age by behavioral response by birth WLZ (high vs. low) was highly significant (p < .01) in some, although not all models. To examine whether the behavioral response to water predicted different growth patterns, we repeated the analyses described above in the sample of infants who received water prior to heel stick. Finally, we also repeated the analyses described above, including both the water and sucrose samples simultaneously in the analyses, and then tested the main effect of “condition” (sucrose vs. water) and interaction of condition with each behavioral response to solution.
3.2. Associations between behavioral response to heel stick and future WLZ among infants who received water (and not sucrose) prior to heel stick Table 3 shows the change in WLZ from birth to 18 months, as predicted by age and behavioral response to heel stick in the perinatal period following the delivery of water (and not sucrose), stratified by birth WLZ below the median compared to at or above the median. As in the sucrose group, WLZ increased with age among infants with birth WLZ below the median. As expected, and similar to the sucrose group, infants with birth WLZ below the median showed more rapid increase in WLZ initially that then tapered off with age, as reflected in the significant quadratic terms for age. Unlike in the sucrose group, we did not find significant associations between behavioral response to water and future WLZ in infants with a birth WLZ at or above the median. There was an unexpected association between behavioral response to water and future WLZ among infants with a birth WLZ below the median, however, the interaction term for quiet alert response to solution and solution type (sucrose vs. water) in predicting future WLZ was not significant (see Table 4). We tested the robustness of these findings by rerunning the models in the combined sample of infants who received either sucrose or water prior to heel stick, and testing the interaction of solution type (sucrose vs. water), with behavioral response to heel stick. As shown in Table 4, among the 141 infants with a birth WLZ at or above the median, the association of negative affect and being sleepy following heel stick with future WLZ differed significantly between infants who received sucrose vs. those who received water prior to heel stick. Specifically, negative affect and being sleepy as behavioral responses to heel stick preceded by sucrose predicted future WLZ, while negative affect and being sleepy as behavioral responses to heel stick preceded by water did not. We considered that differential attrition over time could have affected our results. We therefore reran the models predicting WLZ from birth to 18 months including only those infants with complete data for WLZ at birth, 9 months, and 18 months and found no significant differences in the pattern of results.
3. Results Characteristics of the sample are shown in Table 1. The sample was about half male with a mean gestational age of 39.7 (SD 1.1) weeks and mean birthweight of 3.3 (SD 0.4) kilograms. As expected, sucrose was more effective than water in reducing negative affect [81.5% (SD 16.0%) vs 86.8% (SD 12.6%), p = .003] and increasing quiet alert behavior [5.2% (SD 10.2%) vs. 2.1% (SD 5.4%), p = .001] following the heel stick. 3.1. Associations between behavioral response to heel stick and future WLZ among infants who received sucrose prior to heel stick
4. Discussion
Table 2 shows the change in WLZ from birth to 18 months, as predicted by age and behavioral response to heel stick in the perinatal period following the delivery of sucrose, stratified by birth WLZ below the median compared to at or above the median. WLZ increased with age among infants with birth WLZ below the median. As expected, infants with birth WLZ below the median as well as those at or above the median showed more rapid increase in WLZ initially that then tapered off with age, as reflected in the significant quadratic terms for age. Overall, we found that the association between behavioral response to sucrose and future WLZ was most robust among infants with higher birth WLZ. The associations of negative affect and sleepiness with
This study found that a greater analgesic effect of sucrose in the newborn period was associated with greater increases in WLZ, particularly among infants with higher birth WLZ. The observation that behavioral response to heel stick preceded by water (and not sucrose) was not associated with future WLZ supports the conceptual model that analgesic effects of sucrose are mechanistically related to future WLZ in infancy. We did not find support for the alternative hypothesis that general behavioral response to heel stick, independent of sucrose analgesic effects, predicts future WLZ. In addition, these results were 3
Sex (n, %) Female Male Family members in household (n, SD) Place of residence (n, %) Urban Rural Maternal education ≥ high school (n, %) Gestational age (weeks, mean, SD) Birthweight (kg, mean, SD) Birthweight z-score (mean, SD) Any breastfeeding at 9 months (n, %) Yes No Duration of heel stick procedure (seconds, mean, SD) WLZ (mean, SD) Birth 9 months 18 months Δ WLZ (mean, SD) Birth to 9 mos Birth to 18 mos 9 mos–18 mos Behavioral response (% time, mean, SD) Negative affect Quiet alert Sleepy
Characteristic
80 (52.0%) 74 (48.0%) 3.8 (1.3)
40 (26.3%) 112 (73.7%) 50 (32.7%) 39.7 (1.0) 3.3 (0.4) −0.4 (0.8)
137 (89.0%) 17 (11.0%) 137.8 (83.9)
0.2 (1.1) 1.0 (1.2) 0.6 (1.0) 0.8 (1.4) 0.4 (1.4) −0.4 (0.8)
81.5 (16.0) 5.2 (10.2) 13.2 (13.6)
65 (24.5%) 200 (75.5%) 88 (32.8%)
39.7 (1.1)
3.3 (0.4) −0.3 (0.8)
233 (86.0%) 38 (14.0%) 136.7 (79.6)
0.2 (1.0) 1.0 (1.1) 0.7 (1.0)
0.8 (1.3) 0.4 (1.3) −0.3 (0.8)
83.8 (14.8) 3.9 (8.6) 12.3 (13.0)
N = 154
N = 271
134 (49.4%) 137 (50.6%) 3.8 (1.2)
Sample receiving sucrose prior to heel stick
Total analytic sample
Table 1 Characteristics of infants in the analytic sample.
4 86.8 (12.6) 2.1 (5.4) 11.0 (12.2)
0.7 (1.2) 0.5 (1.2) −0.2 (0.8)
0.2 (1.0) 0.9 (1.1) 0.7 (1.0)
96 (82.0%) 21 (18.0%) 135.2 (73.7)
3.4 (0.3) −0.2 (0.8)
39.7 (1.1)
25 (22.1%) 88 (77.9%) 38 (33.0%)
54 (46.2%) 63 (53.8%) 3.8 (1.1)
N = 117
Sample receiving water prior to heel stick
N (%) or mean (SD)
.003 .001 .19
.64 .78 .12
.93 .56 .45
.79
.17 .15 .10
.69
.95
.43
.73
.34
p-value (sucrose vs. water)
82.5 (11.0) 2.8 (6.3) 14.5 (11.8)
0.2 (1.2) −0.4 (1.2) −0.4 (0.7)
1.0 (0.8) 1.2 (1.2) 0.7 (1.0)
65 (85.5%) 11 (14.5%) 134.0 (79.2)
3.5 (0.4) 0.0 (0.8)
39.7 (0.9)
18 (24.0%) 57 (76.0%) 21 (28.0%)
34 (44.7%) 42 (55.3%) 3.9 (1.4)
N = 76
80.6 (19.6) 7.5 (12.6) 11.8 (15.0)
88.8 (11.6) 1.0 (3.5) 10.1 (11.5)
0.2 (1.1) 0.0 (0.9) −0.2 (0.8)
0.8 (0.5) 1.1 (1.1) 0.9 (0.9)
−0.6 (0.6) 0.8 (1.2) 0.6 (1.0) 1.5 (1.2) 1.2 (1.2) −0.4 (0.9)
53 (81.5%) 12 (18.5%) 139.3 (78.1)
3.5 (0.2) 0.1 (0.6)
39.9 (1.1)
13 (20.3%) 51 (79.7%) 23 (36.5%)
31 (47.7%) 34 (52.3%) 3.9 (1.1)
N = 65
72 (92.3%) 6 (7.7%) 141.6 (88.6)
3.1 (0.3) −0.7 (0.6)
39.7 (1.1)
22 (28.6%) 55 (71.4%) 29 (37.2%)
46 (59.0%) 32 (41.0%) 3.7 (1.3)
N = 78
83.9 (13.7) 3.6 (6.9) 12.4 (13.3)
1.4 (1.1) 1.2 (1.3) −0.1 (0.9)
−0.7 (0.7) 0.7 (1.1) 0.5 (1.2)
41 (82.0%) 9 (18.0%) 129.5 (68.8)
3.2 (0.3) −0.6 (0.8)
39.5 (1.2)
12 (25.0%) 36 (75.0%) 14 (28.0%)
22 (44.0%) 28 (56.0%) 3.6 (1.0)
N = 50
birth WLZ < median
birth WLZ ≥ median
birth WLZ ≥ median
birth WLZ < median
Sample receiving water prior to heel stick
Sample receiving sucrose prior to heel stick
.008 < .0001 .24
< .0001 < .0001 .45
< .0001 .08 .27
.84
< .0001 < .0001 .23
.32
.50
.73
.32
.24
p-value (birth WLZ ≥ vs. < median x condition (sucrose vs. water)
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Table 2 Association of behavioral response to sucrose with WLZ from birth to 18 months stratified by birth WLZ (n = 154). Birth WLZ below the median (n = 78)a Age Negative affect 5.92 (0.78)*** Quiet alert 5.60 (0.87)*** Sleepy 5.86 (0.76)*** Birth WLZ at or above the median (n = 76)a Negative affect −1.47 (0.73)* Quiet alert −1.25 (0.74) Sleepy −1.33 (0.76)
Age x age
Behavioral response
Age x behavioral response
−1.00 (0.15)*** −1.00 (0.15)*** −1.00 (0.15)***
−0.16 (0.36) 0.16 (0.57) 0.16 (0.46)
0.06 (0.04) 0.00 (0.06) −0.10 (0.05)
−0.33 (0.13)* −0.32 (0.13)* −0.31 (0.13)*
−2.31 (0.64)** 1.51 (1.22) 1.64 (0.63)*
−0.14 (0.06)* 0.17 (0.11) 0.08 (0.06)
*p < .05; **p < .01; ***p < .001. a All models controlled for prenatal and postnatal iron supplementation, birth weight-for-length z-score, whether the infant was breastfed vs. not at 9 months, and duration of the heel stick procedure; age centered at mean of 9 months to reduce multicollinearity between linear and quadratic term; behavioral responses centered at median value for that response. Dependent variable is WLZ*100. Values are fixed effect beta estimate (standard error).
Fig. 1. WLZ trajectory among infants with higher birth WLZ, stratified by higher vs. lower negative affect during newborn heel stick following sucrose administration.
Fig. 2. WLZ trajectory among infants with higher birth WLZ, stratified by higher vs. lower sleepiness during newborn heel stick following sucrose administration.
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Table 3 Association of behavioral response to water with WLZ from birth to 18 months stratified by birth WLZ (n = 117). Birth WLZ below the median (n = 50)a Age Negative affect 4.84 (1.03)*** Quiet alert 4.42 (1.10)*** Sleepy 4.97 (1.07)*** Birth WLZ at or above the median (n = 65)a Negative affect 0.84 (0.85) Quiet alert 1.12 (0.87) Sleepy 0.81 (0.83)
Age x age
Behavioral response
Age x behavioral response
−0.81 (0.19)*** −0.81 (0.19)*** −0.82 (0.20)***
−1.42 (0.80) 3.28 (1.44)* 0.38 (0.80)
−0.18 (0.09) 0.30 (0.15) 0.07 (0.09)
−0.30 (0.17) −0.30 (0.17) −0.30 (0.17)
0.66 (0.74) −2.93 (2.15) −0.34 (0.74)
0.00 (0.07) −0.27 (0.23) 0.02 (0.07)
*p < .05; **p < .01; ***p < .001. a All models controlled for prenatal and postnatal iron supplementation, birth weight-for-length z-score, whether the infant was breastfed vs. not at 9 months, and duration of the heel stick procedure; age centered at mean of 9 months to reduce multicollinearity between linear and quadratic term; behavioral responses centered at median value for that response. Dependent variable is WLZ*100. Values are fixed effect beta estimate (standard error).
disease hypothesis posits that fetal programming prenatally, such as through epigenetic changes, alters obesity risk (Gillman, 2005). Infant birthweight is one marker of the intrauterine environment. Birthweight or weight-for-length at birth as a marker of adiposity may be associated with neonatal behavioral response to sucrose or may moderate links between behavioral response to sucrose and rate of weight gain. The intrauterine environment is a powerful mediator of obesity risk and a contributor to birthweight (Oken & Gillman, 2003). As others have hypothesized (Portella & Silveira, 2014), it is possible that substances produced by the placenta or epigenetic changes (Gillman & Ludwig, 2013) may promote neurobiological changes in the infant brain linking sweet taste to drive to eat. Just as there is individual variability in the soothing effects of comfort foods in adults (Dallman et al., 2003), it is possible that certain infants, especially those of greater birth weight, are programmed, whether genetically, epigenetically, or from exposure in utero, to have greater opioid response to sweet foods in early life. In one study, greater birth weight was associated with more robust hedonic response to sweet taste in the newborn period (Ayres et al., 2012). In infants exposed to gestational diabetes, and thus more likely to be of a greater birth weight, increased soothability in infancy was associated with later early childhood obesity (Faith et al., 2019) and using food to soothe has been linked to infant weight gain (Stifter & Moding, 2015). Perhaps infants with programmed greater reward response to sweet taste respond robustly to food when stressed and thus their parents use food to soothe more often due to the learned effectiveness. Our data support that the individual variability in the analgesic effects of sucrose and links to subsequent weight gain may be modified by birth weight, but these questions warrant additional investigation. There are also important developmental effects to consider. The analgesic effect of sucrose seems to decline developmentally, being most potent in the newborn period, at least in rats (Anseloni et al.,
independent of the infant's birth weight-for-length z-score, whether or not the infant was breastfed, and the duration of the heel stick procedure. Overall, our findings are consistent with the hypothesized conceptual model that a more robust opioid response to sucrose detectable in the newborn period confers future obesity risk, potentially mediated through hedonic response to sweet taste and greater dietary intake of sweet foods. Behavioral response to intraoral sucrose during the newborn heelstick may be an observable behavioral indicator of future obesity risk and therefore have clinical implications for delivering preventive interventions to subgroups of infants at risk. The rate of weight gain in the first year of life is a robust risk factor for obesity later in childhood and into adulthood, independent of prenatal factors or birth weight (Baird et al., 2005; Dennison, Edmunds, Stratton, & Pruzek, 2006; Ong & Loos, 2006; Taveras et al., 2011). Preventing rapid weight gain in infancy is an important target for obesity prevention. However, the mechanisms of rapid weight gain in the first year of life are unknown (Lumeng, Taveras, Birch, & Yanovski, 2015). Eating behavior is a likely contributor to differential rates of weight gain. Infants with a vigorous sucking pattern (Agras, Kraemer, Berkowitz, & Hammer, 1990; Agras, Kraemer, Berkowitz, Korner, & Hammer, 1987; Waterland, Berkowitz, Stunkard, & Stallings, 1998), and whose mothers rate them as having a “big appetite” (Llewellyn, van Jaarsveld, Johnson, Carnell, & Wardle, 2010) gain more weight in infancy. Our findings suggest that newborn analgesic response to intraoral sucrose may be an additional behavioral indicator of risk for rapid infant weight gain. We also found that the associations between the analgesic effects of sucrose and future weight gain were more robust among infants with higher birth WLZ. The mechanism underlying this finding are unclear. The intrauterine environment is associated with the offspring's obesity risk, though the mechanisms of effect are only beginning to be elucidated (Oken & Gillman, 2003). The developmental origins of health and
Table 4 Association of behavioral response to water or sucrose with WLZ from birth to 18 months stratified by birth WLZ (n = 269). Birth WLZ below the median (n = 128)a Age
Age x age
Negative affect 5.50 (0.63)*** −0.93 Quiet alert 5.24 (0.69)*** −0.93 Sleepy 5.58 (0.62)*** −0.93 Birth WLZ at or above the median (n = 141)a Negative affect −0.13 (0.54) −0.31 Quiet alert −0.11 (0.57) −0.31 Sleepy −0.22 (0.56) −0.31
Behavioral response
Age x behavioral response
Sucrose vs. water
Sucrose/water x behavioral response
(0.12)*** (0.12)*** (0.12)***
−0.68 (0.67) 2.24 (1.27)† 0.02 (0.69)
0.02 (0.03) 0.04 (0.05) −0.05 (0.04)
3.89 (11.56) 8.58 (12.65) 3.77 (11.52)
0.39 (0.75) −1.78 (1.38) 0.17 (0.81)
(0.11)** (0.11)** (0.11)**
0.55 (0.67) −2.98 (2.14) −0.32 (0.68)
−0.05 (0.04) 0.05 (0.10) 0.04 (0.04)
−9.98 (10.35) −9.26 (10.93) −11.33 (10.62)
−2.79 (0.87)** 4.38 (2.42)† 1.94 (0.87)*
†p < .10, *p < .05; **p < .01; ***p < .001. a All models controlled for prenatal and postnatal iron supplementation, birth weight-for-length z-score, whether the infant was breastfed vs. not at 9 months, and duration of heel stick procedure; age centered at mean of 9 months to reduce multicollinearity between linear and quadratic term; behavioral responses centered at median value for that response. Dependent variable is WLZ*100. Sucrose (=1), Water (0). Values are fixed effect beta estimate (standard error). 6
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2002). In addition, preference for sweet taste declines in adolescence (Desor & Beauchamp, 1987). While we found that the analgesic properties of sucrose were more robust among infants with higher WLZ, others have found that at school age, the analgesic properties of sucrose are weaker among overweight children (Pepino & Mennella, 2005). The analgesic properties of sucrose, and their association with appetitive drive and weight gain, may change developmentally. These questions require further study. Interpretation of these findings should note the study limitations. The longitudinal design is a strength, but attrition was high. There were missing data due to attrition, but our sensitivity analysis did not indicate that this attrition affected the results. Results may not be generalizable to other study populations outside infants born in China. It may be particularly worth examining whether these findings extend to other populations given that the weight-for-length z-scores of this cohort were, though still well within the normal range, above average compared to international references at 9 and 18 months. In addition, 7% of infants in the overall sample were excluded from the protocol because they were crying prior to protocol initiation. This group could represent infants who are particularly difficult to soothe and these findings may therefore not be generalizable to infants who are especially difficult to soothe. Tighter experimental control in the form of standardizing the duration of the painful stimulus would increase confidence in the study findings, but is not possible due to ethical concerns in extending the duration of the painful stimulus for experimental reasons only among healthy infants. Likewise, shortening the duration of the painful stimulus to achieve consistency across infants is also not possible since the primary purpose of the procedure was to obtain a blood sample, and the procedure could not be terminated early without a sufficient blood sample simply for the purposes of this study. In addition, a within-subjects design in which the same infants received sucrose versus water in two painful procedures would increase confidence in the findings, but is not ethically possibly given that healthy infants undergo only one painful heel stick. Despite these limitations, the study was able to describe prospective associations between the analgesic effects of sucrose at birth and future growth, which to our knowledge has not been previously described. In summary, a greater analgesic effect of sucrose in the newborn period was associated with greater rate of weight gain from birth to age 18 months. This effect was stronger among infants with higher birth WLZ. The opioid response to sweet taste may be an important driver of infant appetite and in turn, infant rate of weight gain. Individual differences in behavioral response to sweet taste detectable in infancy may contribute to obesity risk and may be a novel marker for those at risk and mechanistic intervention target for obesity prevention.
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