Early lactase enzyme supplementation: Efficacy to promote growth and feeding tolerance in preterm infants: A randomized controlled trial

Abstract

BACKGROUND

Transient lactase deficiency is common in preterm infants, which may contribute to feeding intolerance, poor growth, and adverse clinical outcomes. Early lactase enzyme supplementation can improve the clinical manifestations produced by lactose intolerance in preterm infants with better weight gain and rapid feeding increment.

AIM

To evaluate the efficacy and safety of lactase enzyme supplementation for improving feeding tolerance and promoting growth without adverse outcomes in Egyptian preterm infants.

METHODS

This prospective, randomized, double-blind, controlled trial included a total of 109 preterm infants born before 34 weeks’ gestation; 55 received lactase supplementation and 54 served as controls. Clinical signs of feeding intolerance, growth parameters, stool reducing substances, stool pH, laboratory findings, and other parameters such as hospital stay duration and patient outcome were assessed over 2 weeks.

RESULTS

The intervention group had lower gastric residuals at week 1 (P = 0.0002) and week 2 (P = 0.003), lower abdominal distension at week 1 (P = 0.007) and week 2 (P < 0.001), fewer emesis attacks at week 1 (P = 0.001), and a lower incidence of diarrhea at week 1 (P = 0.004) and week 2 (P = 0.002). Negative stool reducing substances were more frequent in the intervention group at week 1 (P = 0.011) and week 2 (P < 0.001), with significant in-group improvement only in the intervention arm (P < 0.001). Stool pH was higher in the intervention group at week 1 (P < 0.0001) and week 2 (P < 0.0001). Weight gain was greater (P < 0.0001), while necrotizing enterocolitis (NEC) was less frequently reported in the intervention group (P = 0.0448).

CONCLUSION

Lactase supplementation can improve feeding tolerance symptoms, stool pH, and daily weight gain, and may contribute to a reduction in NEC incidence in preterm infants.

Key Words: Lactase supplementation; Preterm infants; Feeding intolerance; Weight gain; Necrotizing enterocolitis

Core Tip: This randomized, double-blind controlled trial evaluated lactase enzyme supplementation in preterm infants born before 34 weeks of gestation. Lactase supplementation improved feeding tolerance by reducing gastric residuals, abdominal distension, emesis, and diarrhea. It was also associated with improved stool reducing-substance results, higher fecal pH, and greater daily weight gain. In addition, fewer infants developed necrotizing enterocolitis in the lactase group. These findings suggest that lactase supplementation may be a safe and useful adjunct to enteral feeding in preterm infants.

INTRODUCTION

Providing safe and optimal nutrition for preterm infants remains one of the most important and challenging responsibilities to achieve optimal growth. These two features are of significant importance in the preparation of suitable nutritional varieties in these delicate infants[1].

Lactose represents almost 40% of energy in preterm infants, and it can also promote the absorption of various nutrients such as calcium and phosphorus present in breast and formula milk[2]. Lactase activity displays an exact configuration for development in the premature infant, as it correlates not only with post-conceptional age but also with lactose ingestion. Developmental lactase deficiency is detected in premature infants as lactase-expressing enterocytes in the small intestine only start to develop in the third trimester or at a gestational age of at least 34 weeks, and by 35 to 38 weeks, it reaches 70% of that found in term infants and peaks at 40 weeks[3].

The incidence of lactose intolerance (LI) or malabsorption is about 70% in premature infants and 30% in term infants[2]. This condition is characterized by emesis, distention, bloating, watery diarrhea, flatulence, and abdominal pain[4]. Those symptoms lead to recurrent feeding interruption, and prolonged untreated neonatal LI can lead to chronic diarrhea, extrauterine growth retardation, osteopenia of prematurity, and other long-term risks in newborns[5].

Necrotizing enterocolitis (NEC) is a progressive disease process, usually with a high mortality rate between 30% and 50%. While its exact cause is unclear, its link to LI is unestablished, and early symptoms of NEC may be misinterpreted as LI in some cases. On the other hand, it is reported that lactase supplementation in preterm neonates with either breast or formula milk is not associated with an increased risk of NEC[6].

Early diagnosis and proper treatment of LI are crucial for better prognosis, but there are no established guidelines, particularly in preterm infants[7]. Diagnostic modalities include clinical symptoms, the fecal reducing sugar test, and diagnostic elimination. Currently, available treatment options encompass lactase supplementation without breastfeeding interruption, probiotics with β-galactosidase activity as adjuvant therapy, and a lactose-free/low-lactose formula in some cases[8].

Multiple studies have shown that evidence-based lactase enzyme preparations for ≥ 2 weeks added to breast milk or infant formula for preterm infants are the first-line treatment of LI, with wide efficacy and safety, and have a better outcome than using a lactose-free/low-lactose formula. Routine use of a lactose-free/low-lactose formula in preterm infants is not recommended and significantly increases the risk of malnutrition and adverse effects on neurological development. Early use of the lactase enzyme with feeding initiation is still controversial without significant evidence of its efficacy and safety[9].

Therefore, this study aimed to assess the effectiveness and safety of early lactase enzyme supplementation for the promotion of growth and feeding tolerance in Egyptian preterm infants.

MATERIALS AND METHODS

Study design and setting

This prospective, randomized clinical trial was conducted on 115 premature infants born before 34 weeks’ gestational age, selected from the neonatal intensive care units of Cairo University Children’s Hospitals, Egypt, during the period from February 2022 to February 2023. The study was approved by the Research Ethics Committee of Cairo University Faculty of Medicine (approval No. MD-33-2022) and retrospectively registered on ClinicalTrials.gov (ID: NCT07494123) to ensure transparency and public availability of the trial data. Written informed consent was secured from all parents or caregivers of the studied cases before enrollment.

Eligibility criteria

Inclusion criteria were preterm infants born before 34 weeks’ gestational age who had been prescribed to start enteral feeding, with absence of gastrointestinal disorders including NEC. Exclusion criteria were infants with congenital heart disease or other serious congenital malformations; cow milk protein allergy symptoms such as distention or increased gastric residual; neonatal sepsis; or legal guardians unwilling to sign the informed consent.

Sample size

The sample size was calculated using the formula n = (Z_α/2 + Z_β)² × 2 × σ²/d², where Z_α/2 is the critical value of the normal distribution at α/2, Z_β is the critical value at β, σ² is the population variance, and d is the expected difference between the two groups. For a 95% confidence level, Z_α/2 was 1.96, and for 80% study power, Z_β was 0.84. Based on data reported by Wang et al[2], who performed a randomized controlled trial on 60 preterm infants to ensure the efficacy and safety of lactase enzyme in LI improvement, the mean weight gain rate was 19 ± 7 g/day in the lactase-treated group compared with 15 ± 7 g/day in the control group. Accordingly, the estimated sample size was at least 49 preterm infants in each group.

Randomization and grouping

This prospective, double-blind, controlled study randomized subjects consecutively into group A (intervention group) or group B (control group). Randomization was performed using a computer-generated random sequence. Allocation concealment was ensured using sequentially numbered, sealed, opaque envelopes. Outcome investigators were blinded to group allocation to minimize bias.

Intervention

Therapeutic intervention was started once feeding had been initiated. A total of 115 preterm infants were randomly assigned to two groups: 57 infants were allocated to the intervention group and received lactase supplementation, while 58 infants were assigned to the control group. Infants in the intervention group received one drop of lactase enzyme (Easycol Baby drops^®; 1 drop = 50 μL = 150 acid lactase unit) added to 20 mL of premature formula or expressed breast milk, followed by incubation for 30 minutes at room temperature. In breastfed infants, 5 drops were administered before each direct breastfeeding session. Lactase enzyme supplementation was continued for 2 weeks based on current evidence supporting treatment for ≥ 2 weeks for developmental LI, aligning with intestinal recovery timelines. Notably, prolonging the intervention duration does not increase clinical benefits[9]. Infants in the control group received untreated formula or breast milk, and both groups received the same standard feeding protocol.

Clinical evaluation and laboratory investigations

All included preterm infants underwent baseline clinical and laboratory assessment. History taking and examination focused on infection risk factors, anthropometric measurements plotted on the Fenton growth chart[10], gestational age assessment using antenatal ultrasound and the New Ballard Score[11], and detection of congenital anomalies, sepsis manifestations, and signs of feeding intolerance and NEC. Laboratory evaluation included complete blood count (CBC), quantitative C-reactive protein (CRP), blood culture, stool analysis, fecal pH, and stool reducing substances.

Assessment of feeding intolerance and NEC

NEC diagnosis and staging were performed using the Modified Bell’s criteria, based on clinical, radiographic, and laboratory findings[12]. Signs of feeding intolerance were monitored throughout the study period. Gastric residual volume was considered significant when the residual exceeded 30%-50% of the previous feed in two consecutive meals. Abdominal distention was defined as an increase in abdominal girth of more than 1.5 cm per day or the presence of dilated bowel loops clinically or by ultrasound, in accordance with the criteria described by Porzi et al[13]. Diarrhea was defined as the passage of 3 or more loose or liquid stools per day, or more frequently than normal for the individual case, although frequent pasty stools in exclusively breastfed cases were not defined as diarrhea[14].

Follow-up

Each neonate enrolled in the study was followed up at the end of the first and second week after the intervention with recording of sepsis and NEC incidence, duration of hospital admission, and outcome until discharge. Follow-up data included anthropometric parameters, daily feeding increments and weight gain, and gastrointestinal symptoms such as gastric residual, abdominal distention, and diarrhea. Laboratory investigations, including CBC and CRP, stool analysis, fecal pH, and reducing substances in stool were also evaluated at the end of the first and second weeks.

Fecal pH measurement

A fresh watery stool sample was homogenized and centrifuged before analysis. Fecal pH was measured in a fresh stool sample using nitrazine paper. Normally, fecal pH ranges between 6.0 and 6.5, while a fecal pH below 5.5 indicates acidic stool and may suggest carbohydrate malabsorption.

Benedict’s test for reducing substances in stool

Reducing substances in stool were assessed using Benedict’s test. The stool sample was collected after spontaneous defecation in a disposable plastic container with a sealed lid, taking care to avoid contamination with urine or genital secretions. Samples were sent to the laboratory within 4 hours of passage and stored at 2-8 °C until analysis. For testing, one volume of stool was mixed with an equal volume of distilled water, homogenized, and centrifuged at 3000 rpm for 10 minutes. After centrifugation, 2.5 mL of Benedict’s reagent, prepared from sodium citrate and copper sulfate, was added to 10 drops of the supernatant, and the tube was heated for 10 minutes.

The principle of Benedict’s test depends on the change in reagent color according to the sugar content in the feces. In infants, the normal carbohydrate content in stool ranges from 0% to 0.3%. A carbohydrate level of 0.3%-0.5% indicates a slight excess that is usually not considered abnormal in the absence of poor appetite or weight loss. However, stool carbohydrate content above 1% suggests a high probability of LI[15].

Statistical analysis

Statistical analysis was performed using SPSS version 27.0 for Macintosh. Numerical data were expressed as mean ± SD, whereas categorical data were presented as n (%). The independent t-test was used to compare parametric variables between two groups. One-way ANOVA was used to analyze differences among means of more than two groups, followed by post hoc testing to determine which groups differed significantly. Qualitative variables were compared using the χ² test. Pearson’s correlation coefficient was used to assess significant correlations between quantitative variables. A P value < 0.05 was considered statistically significant.

RESULTS

The study was conducted on one hundred and twenty-four premature patients admitted to the neonatal intensive care units. Fifteen patients were excluded from the study: 4 patients due to early-onset sepsis, 5 died, 5 were diagnosed with NEC, and 1 was discharged before the 2-week observation period; thus, 109 cases completed the study (Figure 1).

Figure 1 CONSORT flow chart of the studied cases. EOS: Early onset sepsis; NEC: Necrotizing enterocolitis.

There were no statistically significant differences between the two studied groups regarding baseline demographics, admission diagnosis, feeding type, or history of maternal comorbidity (Table 1).

Table 1 Clinical and demographic characteristics between the studied groups, n (%)/mean ± SD.

Variable	Intervention group (n = 55)	Control group (n = 54)	P value
Male gender	26 (47.3)	27 (50.0)	0.4629
GA (weeks)	31.5 ± 1.84	31.5 ± 1.57	0.976
Birth weight (kg)	1.5 ± 0.289	1.51 ± 0.343	0.855
Mode of delivery (CS)	45 (81.8)	39 (72.2)	0.2616
PROM incidence	15 (27.3)	12 (22.2)	0.6582
Admission diagnosis
RDS	47 (85.4)	41 (75.9)
PH	6 (11)	9 (16.7)	0.204
IUGR	1 (1.8)	0 (0)
HDFN	0 (0)	3 (5.5)
HIE	1 (1.8)	1 (1.9)
Feeding type
Exclusive breast milk	2 (3.6)	1 (1.9)	0.3623
PT formula	46 (83.6)	38 (70.4)
Breast and PT formula	5 (9.0)	11 (20.4)
AR	2 (3.6)	4 (7.4)
History of maternal comorbidity	16 (29)	23 (42.5)	0.141

GA: Gestational age; CS: Cesarean section; PROM: Premature rupture of membranes; RDS: Respiratory distress syndrome; PH: Pulmonary hypertension; IUGR: Intrauterine growth retardation; HDFN: Hemolytic disease of the fetus and newborn; HIE: Hypoxic-ischemic encephalopathy; PT: Preterm; AR: Anti-regurgitation.

There were no statistically significant differences between the two studied groups regarding laboratory findings at study entry or at the 2^nd week, including Hb at study entry (P = 0.131) and 2^nd week (P = 0.895), total leukocytic count at study entry (P = 0.691) and 2^nd week (P = 0.053), platelets at study entry (P = 0.956) and 2^nd week (P = 0.599), and CRP at study entry (P = 0.786) and 2^nd week (P = 0.486) (Table 2).

Table 2 Laboratory findings between the studied groups at study entry and at the 2^nd week, mean ± SD.

Variable	Intervention group (n = 55)	Control group (n = 54)	P value
Hb (g/dL)
At study entry	16.55 ± 2.7	15.8 ± 2.4	0.131
At 2nd week	12.95 ± 2.16	12.89 ± 2.4	0.895
TLC (× 103/mL)
At study entry	11.0 ± 4.6	10.6 ± 4.94	0.691
At 2nd week	11.94 ± 5.16	14.2 ± 6.759	0.053
PLT (× 103/mL)
At study entry	255.6 ± 87.82	256.9 ± 104.4	0.956
At 2nd week	282.7 ± 139.1	296.3 ± 130.2	0.599
CRP (mg/L)
At study entry	3.1 ± 2.5	3.27 ± 1.98	0.786
At 2nd week	10.3 ± 30.2	7.1 ± 15.51	0.486

Hb: Hemoglobin; TLC: Total leukocytic count; PLT: Platelets; CRP: C-reactive protein.

There were no statistically significant differences between the two studied groups regarding growth parameters at either the 1^st or 2^nd week, including weight at 1^st week (P = 0.899) and 2^nd week (P = 0.199), height at 1^st week (P = 0.854) and 2^nd week (P = 0.617), and head circumference at 1^st week (P = 0.658) and 2^nd week (P = 0.924) (Figure 2 and Table 3).

Figure 2 Growth parameters including weight and height at the 1^st and 2^nd week of observation in both groups. A: Weight; B: Height.

Table 3 Anthropometric parameters between the studied groups at study entry and at the 2^nd week, mean ± SD.

Variable	Intervention group (n = 55)	Control group (n = 54)	P value
Weight (kg)
1st week	1.436 ± 0.268	1.42 ± 0.30	0.899
2nd week	1.706 ± 0.299	1.62 ± 0.318	0.199
Height (cm)
1st week	41.2 ± 2.69	41.13 ± 2.82	0.854
2nd week	43.3 ± 2.95	43.0 ± 2.903	0.617
HC (cm)
1st week	29.14 ± 1.76	29.29 ± 1.781	0.658
2nd week	30.79 ± 1.85	30.8 ± 1.78	0.924

HC: Head circumference.

Gastric residual was significantly lower in the intervention group than in the control group at both the 1^st week (23.6% vs 59.3%, P = 0.0002) and the 2^nd week (16.4% vs 42.6%, P = 0.003). Abdominal distension was also significantly lower in the intervention group at the 1^st week (56.4% vs 81.5%, P = 0.007) and the 2^nd week (25.5% vs 74.1%, P < 0.001). Emesis was significantly lower in the intervention group at the 1st week (9.1% vs 35.2%, P = 0.001), whereas emesis at the 2^nd week was not significantly different (P = 0.62). Diarrhea was significantly lower in the intervention group at the 1^st week (5.5% vs 25.9%, P = 0.004) and the 2^nd week (1.8% vs 20.4%, P = 0.002) (Table 4).

Table 4 Feeding intolerance parameters between the studied groups at the 1^st and 2^nd week, n (%).

Variable	Intervention group (n = 55)	Control group (n = 54)	P value
Gastric residual
1st week	13 (23.6)	32 (59.3)	0.0002
2nd week	9 (16.4)	23 (42.6)	0.003
Abdominal distension
1st week	31 (56.4)	44 (81.5)	0.007
2nd week	14 (25.5)	40 (74.1)	< 0.001
Emesis
1st week	5 (9.1)	19 (35.2)	0.001
2nd week	1 (1.8)	2 (3.7)	0.62
Diarrhea
1st week	3 (5.5)	14 (25.9)	0.004
2nd week	1 (1.8)	11 (20.4)	0.002

Reducing substance in stool differed significantly between the two studied groups at both the 1^st and 2^nd week. At the 1^st week, the intervention group showed a significantly higher proportion of negative results than in the control group (40.0% vs 22.2%, P = 0.01185), while higher grades of positivity, particularly ++, were more frequent in the control group (20.4% vs 3.6%). At the 2^nd week, this difference became more pronounced, as negative results increased markedly in the intervention group compared with the control group (69.1% vs 13.0%, P < 0.001), whereas +, ++, and +++ results remained more frequent in the control group. In the in-group comparison, the intervention group showed a statistically significant change over time (P < 0.001), whereas the control group did not show a significant change (P = 0.2274) (Table 5).

Table 5 Reducing substance (Benedict’s test) in stool at the 1^st and 2^nd week between the studied groups, and in-group comparison, n (%).

Variable	Intervention group (n = 55)	Control group (n = 54)	P value
Reducing substance in stool at 1st week
Negative	22 (40.0)	12 (22.2)	0.01185
Trace (< 500 mg/dL)	5 (9.1)	7 (13.0)
+ (500-1000 mg/dL)	26 (47.3)	23 (42.6)
++ (1000-1500 mg/dL)	2 (3.6)	11 (20.4)
+++ (1500-2000 mg/dL)	0 (0.0)	1 (1.9)
Reducing substance in stool at 2nd week
Negative	38 (69.1)	7 (13.0)	< 0.001
Trace (< 500 mg/dL)	5 (9.1)	3 (5.6)
+ (500-1000 mg/dL)	10 (18.2)	23 (42.6)
++ (1000-1500 mg/dL)	2 (3.6)	18 (33.3)
+++ (1500-2000 mg/dL)	0 (0.0)	3 (5.6)
In-group comparison	P < 0.001	P = 0.2274

Benedict’s test interpretation: Negative: Blue solution; Trace: Green solution; +: Green ppt; ++: Yellow ppt; +++: Orange ppt.

Stool pH was significantly higher in the intervention group than in the control group at both the 1^st week (6.32 ± 0.69 vs 5.7 ± 0.9, P < 0.0001) and the 2^nd week (6.5 ± 0.98 vs 5.3 ± 0.72, P < 0.0001) (Table 6).

Table 6 Stool pH analysis after the 1^st and 2^nd week between the studied groups, mean ± SD.

Stool pH	Intervention group (n = 55)	Control group (n = 54)	P value
1st week	6.32 ± 0.69	5.7 ± 0.9	< 0.0001
2nd week	6.5 ± 0.98	5.3 ± 0.72	< 0.0001

Weight gain was significantly higher in the intervention group than in the control group (18.9 ± 9.5 g/day vs 12.3 ± 6.3 g/day, P < 0.0001), while NEC incidence was significantly lower in the intervention group (5.5% vs 18.5%, P = 0.0448). Days to reach full enteral feeding did not differ significantly between the intervention and control groups (P = 0.250). A negative relationship was observed between the time to achieve full enteral feeding and the rate of weight gain. Sepsis incidence was not significantly different (P = 1.0), hospital stay was not significantly different (P = 0.339), and fate was not significantly different between the two groups, including discharged (P = 1.0) and deceased cases (Figure 3 and Table 7).

Figure 3  Scatter plot analysis of the relationship between time to achieve full enteral feeding and subsequent weight gain in both study groups.

Table 7 Primary and secondary outcomes between the studied groups, n (%)/mean ± SD.

Variable	Intervention group (n = 55)	Control group (n = 54)	P value
Primary outcome
Weight gain (g/day)	18.9 ± 9.5	12.3 ± 6.3	< 0.0001
Days to reach full enteral feeding (days)	15.0 ± 8.24	16.9 ± 8.45	0.250
NEC incidence	3 (5.5)	10 (18.5)	0.0448
Secondary outcome
Sepsis incidence	8 (14.5)	8 (14.8)	1.0
Hospital stay (days)	23.6 ± 8.24	25.7 ± 8.45	0.339
Fate
Discharged	47 (85.5)	46 (85.2)	1.0
Died	8 (14.5)	8 (14.8)

NEC: Necrotizing enterocolitis.

DISCUSSION

Preterm infants frequently develop feeding intolerance because of immature intestinal lactase activity, which may impair nutrient utilization and growth[16]. Although lactase enzyme is the safest and approved line of treatment of LI in preterm infants, early lactase enzyme supplementation is still controversial. Therefore, we included 109 preterm infants born before 34 weeks’ gestation, comparing early lactase supplementation with standard feeding practice.

In the present study, growth parameters including weight and length during the observation period were not significantly higher in the lactase supplement group, and this agrees with Erasmus et al[17], who conducted a double-blind randomized controlled trial (RCT) on 130 preterm infants to evaluate whether lactase-treated preterm feeds enhance weight gain and feeding tolerance in premature infants, and showed that the lactase-treated feed group had significantly higher growth parameters than the other group, which had received untreated feeds.

In our study, the observed signs of LI were recurrent gastric residuals, abdominal distension, emesis, and diarrhea. Abdominal distension was the most commonly observed sign in both studied groups. Similarly, a multicenter, prospective, randomized controlled trial by Zha et al[18] involving 155 preterm infants with LI (gestational age ≤ 34 weeks) found that 56.1% experienced abdominal distension, 21.9% had vomiting, and only a few reported diarrhea.

At the end of the first and second week of observation, the symptoms of LI in our study showed a highly statistically significant difference as regards gastric residual, distention, emesis, and diarrhea, with a lower incidence among the lactase supplement group. A nonrandomized, multicenter study by Chen et al[19], including 117 preterm infants with LI, showed that lactase supplementation effectively treats neonatal LI, promotes weight gain, and does not require discontinuation of breastfeeding.

Benedict’s test is one of the typical methods for the diagnosis of LI in infants and shows all the required characteristic features; besides that, it is economical, quick, and sensitive. Accordingly, Tolipova et al[15] conducted a survey on 60 full-term infants and showed normal passage of fecal carbohydrates, which was not more than 0.05% reduced substances (traces) of lactated drugs group. This agrees with our results, as there was a statistically significant difference between the 2 groups, with 22 negative cases (40%) and 38 cases (69%) in the lactase supplement group at the first and second week, respectively, compared with 12 negative cases (22%) and 7 cases (12.9%) in the control group in both weeks, respectively.

The stool pH was more acidic in the control group than in the lactase supplement group in both weeks. Wang et al[2] included 60 preterm infants with LI in a randomized controlled trial in which one drop of lactase enzyme was added to 20 mL of breast or formula milk for 1 week in one group, while the other group served as the control. Some symptoms of LI were relieved, but there was no significant difference in stool properties and reducing sugar levels.

Feeding tolerance follow-up showed a highly statistically significant difference between the two groups, with a greater feeding increment per day among the lactase supplement group, but Wang et al[2] reported different data at the end of the first week after the intervention, as there was no significant difference in the amount of feeding between the two groups.

Our study showed a highly statistically significant difference in primary outcomes as regards weight gain among the lactase supplement group, with a mean of 18.9 g/day vs 12.3 g/day in the control group; this was in accordance with the randomized double-blind trial conducted by Erasmus et al[17], which reported that the preterm babies in the lactase formula milk group had rapid weight gain and increased serum albumin levels in the early observation period. In contrast to Tan-Dy and Ohlsson[5] in the Cochrane review, there was no significant outcome on weight gain observed despite the addition of lactase enzyme.

One of the primary outcomes in our study was that the duration to reach full enteral feeding was shorter in the lactase supplement group, with no statistically significant difference; similarly, Tan-Dy and Ohlsson[5] reported no evidence of significant benefit regarding the time required to reach full enteral feeding with lactase supplementation. As regards the safety profile of lactase enzyme, NEC incidence was detected in 10 cases (18.5%) in the control group vs only 3 cases (5.5%) in the lactase supplement group, which was statistically significant. In contrast, Erasmus et al[17] reported that NEC incidence was lower in the lactase-treated feeds group but without statistical significance.

Secondary outcomes followed after the end of the study, including late-onset septicemia incidence, terminal fate of patients, and hospital stay, were comparable in the lactase supplement and control groups. This suggests that the use of lactase drops in premature infants is safe and has effectively improved the features of LI in premature infants such as vomiting, gastric retention, and diarrhea, and increased the rate of breast or formula milk feeding in premature infants.

This study was limited by its single-center design, relatively small sample size, and lack of stratification of premature infants into subgroups according to gestational age. Laboratory monitoring of calcium, phosphorus, and albumin as markers of proper lactase activity was not reported in the current study. The short follow-up period and the inclusion of only infants who completed 2 weeks of observation may also limit generalizability and preclude assessment of longer-term growth, recurrent intolerance, and other late outcomes.

CONCLUSION

Lactase enzyme supplementation in preterm babies improved manifestations of LI, including gastric residuals, emesis, abdominal distension, and diarrhea, and was associated with improved stool findings, including normalization of fecal carbohydrates by Benedict’s test and higher stool pH, without reported adverse reactions, including sepsis and NEC. It also significantly enhanced feeding advancement and daily weight gain. Future large-sample RCTs are needed to establish the optimal intervention timing and to evaluate the clinical utility of preventive interventions in extremely or very preterm cohorts. Moreover, essential research should focus on estimating the effects of the ideal initiation time, dosage, duration, and composition of lactase enzyme preparations.

ACKNOWLEDGEMENTS

The authors thank the medical and nursing staff of the neonatal intensive care units at Cairo University Children’s Hospitals for their support with participant recruitment, clinical follow-up, and data collection. The authors also thank the Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, for their assistance with laboratory analyses. The authors are grateful to the parents and legal guardians of the participating infants for their cooperation.