The optimal food for healthy infants is breast milk, which provides an adequate supply of all essential nutrients for growth and bacterial community to develop infant gut microbiome [1
]. Around 50% of the dietary calories received from breast milk and most infant formulas are fats, especially triglycerides, which constitute nearly 95% of the milk fats [3
]. Palmitate represents about 17–25% of the breast milk fatty acids, and around 70% of it is esterified to the sn-2 (ß) position; however, in infant formula, it is predominantly at the sn-1 and sn-3 positions [3
]. Therefore, the absorption of palmitic acid from human milk is much better than in infant formulas, which can be attributed to the high tendency of palmitic acid in infant formulas to create complexes with dietary minerals and form saponified fatty acids. In return, these complexes can lead to a decrease in both minerals and palmitic acid [6
]. The formation of these complexes is usually associated with poor digestion and harder stools [9
]. On the other hand, many reports have mentioned that using formulas similar to human milk’s positional fatty acid profile was associated with better mineral balance, lower fecal calcium excretion, and improved absorption, especially in term and premature infants [6
Therefore, a growing body of evidence has evaluated infant formulas with increased levels of palmitic acid in the sn-2 position to improve infant fat absorption [11
]. The high sn-2 palmitate vegetable oil (BetapolTM
) formula differs from the fat in most infant formulas in that the palmitic acid is predominantly esterified to the sn-2 position of the fat molecule and more closely resembles the palmitic acid in human milk. Fatty acids in the sn-2 position do not readily bind calcium and are easily absorbed [12
]. Studies have shown that infants who consume a formula containing a mixture of high sn-2 formula and the usual vegetable oils have reduced fecal excretion of calcium fatty acid soaps and softer, more frequent stools [6
]. Moreover, many studies have highlighted the significant difference between the human milk and infant formulas in terms of gastrointestinal tolerance; however, they also showed that this difference is substantially reduced when high sn-2 formulas are used [15
According to previous reports, the rate of exclusive breastfeeding in the Gulf Cooperation Council (GCC) countries is low, and a considerable proportion of healthy infants are formula-fed [18
]. The large variety in the commercially available formulas was noted to confuse parents from the GCC and resulted in frequent changes in the utilized formula [20
]. Thus, real-world evidence is critically needed to characterize the outcomes of various infant formulas. Despite high sn-2 formulas exhibiting acceptable efficacy in previous trials, to the best of our knowledge, there are limited data regarding the safety and efficacy of high sn-2 formula in formula-fed and partially breast-fed healthy term infants in GCC countries. Hence, the current prospective study aimed to assess the gastrointestinal tolerance, acceptability by both parents and pediatricians, and safety of high sn-2 infant formula among non-breastfed healthy term infants in the GCC countries.
The present study sheds light on the safety and efficacy of high sn-2 infant formula in healthy non-breastfed infants. Overall, we demonstrated that the high sn-2 infant formula significantly improved the stool characteristics and the gastrointestinal symptoms by the end of the 12th week amongst healthy non-breastfed infants. Our findings showed a significant reduction in the percentages of hard stool and the infants exhibited a less hard stool at the end of the 12th week of the follow-up. Besides, the percentages of pale yellow, green, and black stools decreased significantly at the end of the study’s follow-up.
These findings are in agreement with those of Yao et al., who found that the infants who received the high sn-2 formula were associated with softer stool, reduced stool soaps, and increased bifidobacteria [24
]. Carnielli et al. and Kennedy et al. reported similar findings [10
]. Kennedy et al. [14
] conducted a double-blind, randomized trial (RCT) to estimate the difference between the formula that contained 50% high sn-2 formula and standard formula in term infants. At six and 12 weeks, they showed that the high sn-2 formula was associated with softer stool and reduced proportion of stool soap fatty acids compared to the standard formula. However, they reported no significant difference between both groups in terms of the number of stools per week. In the RCT conducted by Béghin and colleagues [25
], they confirmed the efficacy of the high sn-2 formula compared to the control formula in softening the infants’ stool. Another study by Joyce et al. [17
] also reported that sn2 palmitate in infant formula decreased stool palmitate soaps and promoted softer stools. It is hypothesized that the main cause behind the softening of stool in infants who received high sn-2 is the reduced saturated fatty acids soaps and replacing it with a structured lipid-containing fat blend enriched in sn-2 palmitate [26
Nonetheless, a previous RCT showed no significant difference between the sn-2 formula and the control group in terms of stool consistency [17
]. Such findings can be attributed to the low percentage of palmitic acid sn-2 in the formula they used (39% palmitic acid sn-2) compared to 66% used in the study of Carnielli et al. or Kennedy et al. [10
]. However, this explanation can be challenged by the findings of Litmanovitz et al. [29
] in which there were no differences in stool frequency or consistency at six or 12 weeks between the high and low sn-2 palmitate formulas. However, at 12 weeks, fewer infants in the high sn-2 palmitate group had hard stools than the low sn-2 palmitate group (0% vs. 24%) [29
]. Thus, further trials are warranted to compare the impact of high and low sn-2 palmitate formulas on the stool characteristics of infants.
Infant colic is a collective term usually used to describe irritability and persistent crying (>three hours per day for >three days per week) by infants. Infants with persistent colic are more prone to improper feeding and poor parental engagement [30
]. According to a literature review by Yvan et al., the prevalence of functional constipation in infants was found to be around 15% [31
]. The harder stool may contribute to more intestinal pain and infant crying [29
]. In the present study, we found that the high sn-2 formula reduced the prevalence of colic and abdominal distention declined from 21.4% and 39.9% at baseline to 2.9% and 9.4% at week 12, respectively. Moreover, more than 83% of the included infants showed no regurgitation after 12 weeks from receiving the high sn-2 formula. In the 2014 study by Litmanovitz et al. [29
], it was found that the high-sn-2 formula reduced the percentage of crying infants and the average time spent crying every day. However, these findings should be interpreted cautiously, since it is well-recognized that infant colic improves after three to six months of age [32
]; thus, the observed decline in our study may represent a natural course of infant colic, rather than a significant effect of the infant formula.
Regarding the growth parameters, our study showed a significant increase in the weight of the infants as well as the hip/waist ratio and head circumference. The increase in the weight centile in infants who received sn-2 formula can be attributed to the reduced fat-loss compared to the standard formula [24
]. According to Carnielli et al. [10
], the sn-2 formula was associated with the highest fat absorption compared to other formulas. Interestingly, Zhong and his colleagues [33
] showed that the high sn-2 formula had a similar effect to breastfeeding on body growth and prevention of hard stools. Béghin et al. [25
], reported that the sn-2 formula and standard formula had a comparable effect on the body mass; however, the sn-2 group was associated with increased bone mineral content. This was further supported by Litmanovitz et al. [34
], who showed a significant increase in the bone strength amongst infants receiving a high sn-2 formula that was comparable to human breastfeeding. Consistently, a review by Bar-Yoseph et al. [35
] reported that recent studies have confirmed that sn-2 palmitate increases early bone development and mineralization, influences the formation of the intestinal microflora, could lower the severity and extent of intestinal inflammation, and may have neurobiological effects including early infant crying.
In the present study, we showed that the high sn-2 formula was well-tolerable with a low incidence of side effects. A total of 29 infants (10.5%) reported adverse events, of which only 20.7% of the adverse events were moderate, and none were severe. Béghin et al. [25
] reported a higher incidence of adverse events (36.8%). However, this percentage was much lower than the control group (46.3%). In the study of Yao et al., they showed that 46.7% of the infants who received sn-2 formula had some adverse events; however, they stated that 93.3% of the adverse events were unrelated to feedings and 83.3% were mild in intensity. The most common reported adverse events were pyrexia, cough, and rhinorrhea [24
]. According to the findings of Nowacki et al. [17
], there was no significant difference between the sn-2 formula and the control group in terms of the incidence of adverse events (46.4% vs. 42.6%), respectively. Nevertheless, the feeding-related adverse events were only three adverse events.
Such findings were reflected in the acceptability of both parents and pediatricians. In the present study, we found that the high sn-2 formula’s tolerability was rated as good-to-excellent by the pediatricians and parents. In addition to the good safety profile of the sn-2 formula, this high tolerability suggests that the high sn-2 is a good alternative to the standard formulas. Our study has some limitations. First, the risk of selection bias is high in our study. We selected the patients using a convenience sample, and we could not include a control group to estimate the exact efficacy within and between groups. The lack of a control group represents a significant limitation in the present study, as the observed changes in the stool characteristics and other study’s outcomes may be attributed to the natural progress of the infants themselves, rather than the effect of the formula itself. Second, we did not evaluate the stool fat soaps and the bone mineral mass, and third, there was a lack of a breastfed reference group.