Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06118801 |
| Other study ID # |
HarrranU-FSolmaz-001 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 2023 |
| Est. completion date |
March 2024 |
Study information
| Verified date |
November 2023 |
| Source |
Harran University |
| Contact |
Filiz Solmaz |
| Phone |
+90 414 318 3203 |
| Email |
filizsolmaz[@]harran.edu.tr |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Abstract According to the definition by World Health Organization; births before the
completion of the 37th gestational week are called, preterm birth. Preterm birth is among the
most important causes of mortality and morbidity during infancy. Necrotizing enterocolitis
(NEC) is the most common gastrointestinal emergency encountered in the Neonatal Intensive
Care Unit. The most common risk factors are, preterm birth, enteral feeding and bacterial
colonization.
Late Onset Sepsis (LOS) is one of the most common causes of morbidity and mortality in the
preterm infants. A healthy gut microbiota has a key role in developing and maintaining a
balanced immune response and establishing the intestinal barrier in the immediate postnatal
period. Probiotics come to the fore as means that may be effective in preventing NEC and LOS.
Although it is widely accepted that, breast milk has its own microbiota, the origin of these
bacterial populations in the milk, has not been fully understood. The new information
regarding especially the anaerobic species associated with the intestinal environments that
cannot be found in the aerobic environments, suggests an endogenous route to the mammary
gland through the presence of the entero-mammary pathway.
The aim of this project is to determine the effect of the probiotics added to the maternal
diet on the incidence of encountering NEC and LOS in the preterm infants. The unique value of
this project is that, 80 ml of probiotic yogurt will be given to mothers of the preterm
infants, who still breastfeed their babies, for 20 days and the effects on the baby will be
examined in the scope of the study.
The study has been planned to be conducted as a randomized controlled study in the Neonatal
Intensive Care Unit of Şanlıurfa Training and Research Hospital. The power analysis was
performed with G*Power for the sample size of the study, which has an experimental/control
design structure. The sample size was determined as 50 in total. Data collection tools were
organized as Mother and Infant Introductory Information Form (23 questions), Mother and
Infant Follow-up Form during Probiotic Implementation (7 questions). At the beginning of the
study, all mothers will fill out the mother and baby introductory information form, and the
mothers in the experimental group will be given 80 ml probiotic yogurt support once a day for
20 days. In addition to that, all the babies will be monitored for growth once a week,
throughout the process. Their status of regular breastfeeding, whether they are diagnosed
with NEC and LOS, the time of transition to oral feeding, their bilirubin levels, their
status of receiving phototherapy and their discharge durations will be evaluated, and a
questionnaire that consists of scale questions will be applied after the discharge.
As a result of this project, it is aimed with the probiotic that will be added to maternal
nutrition to reduce the encounter of NEC and LOS in preterm infants, to positively affect the
intestinal microbiota by preventing dysbiosis in these infants, to protect them from very
important problems such as NEC and LOS as well as accelerating the transition to oral
feeding, to help them gain weight, to shorten the duration of receiving phototherapy and
hospitalization by reducing the bilirubin levels.
Description:
Preterm birth is birth that occurs before the completion of the 37th week of pregnancy. It
affects approximately 10% of pregnancies and is a leading cause of perinatal morbidity and
mortality. Preterm infants are at high risk for necrotizing enterocolitis (NEC), sepsis,
death, and lifelong neurodevelopmental and cognitive impairment.
The most important acquired disease of the gastrointestinal tract in preterm infants is NEC,
which is characterized by intestinal necrosis of varying depths and locations and most
commonly affects the terminal ileum and proximal colon. NEC is a devastating disease with
multifactorial etiology that carries a great burden in terms of mortality, morbidity, and
cost to society. It is seen with a frequency of 3-15% in neonatal intensive care units, and
>90% of affected babies are preterm babies under 32 weeks of gestation . According to the
data of the Turkish Neonatology Association, the incidence in very low birth weight (VLBW)
babies is 9.1% . Although its etiology and pathogenesis are not fully understood, it is a
condition characterized by inflammation-related ischemic necrosis of the intestinal mucosa.
Despite early diagnosis and aggressive treatment, it causes 15-30% mortality and is an
important cause of long-term morbidity, especially in VLBW babies. The inflammatory process
initiated in the highly immunoreactive gut in NEC prolongs the effects of the disease
systemically, affecting distant organs such as the brain and placing affected infants at
significantly increased risk for neurodevelopmental delays . One hypothesis suggests that the
main etiological factor for NEC is colonization of the neonatal intestine with an abnormal
microbiota, specifically that NEC typically occurs 8-10 days after birth when anaerobic
bacteria begin to colonize the intestine. In studies examining the effectiveness of probiotic
supplementation in preventing NEC (Evidence Level 1+, Recommendation Level B/C), there was a
significant reduction in overall mortality. concluded Neonatal sepsis is a clinical syndrome
in which there are systemic signs and symptoms of infection in the first month of life and a
specific agent is produced in blood culture. Despite the developments in the field of
neonatology, it is still an important cause of morbidity and mortality. The incidence of
neonatal sepsis varies between 1 and 8.1 per 1000 live births, although it is lower in
developed countries. In our country, the incidence of late-onset sepsis has been reported as
6.4-14.1% and mortality as 0-75%. The incidence of sepsis is 3-10 times higher in preterm
babies than in term babies. Disturbances in the establishment of normal intestinal microbiota
and commensal microbes colonizing the digestive tract may increase the risk of sepsis through
disruption of the mucosal barrier resulting in translocation of luminal contents. Although
the correlation of disruptions in the intestinal microbiota with LOS is known, more
microbiota-based studies are needed for early intervention to prevent LOS in high-risk
infants.
The infant's gut microbiota is a highly dynamic community that is gradually and continuously
shaped in the first days of life. Colonization of the infant microbiome begins at birth, when
infants can acquire many different types of bacteria from the environment, from their
mothers' vagina, skin, and intestines. The immature gut response and changes in the gut
microbiota or abnormal colonization pattern in preterm infants predispose the intestines of
newborns to inflammation and a range of pro-inflammatory and counter-inflammatory cytokine
responses. Microbial translocation or increased permeability to microbial components can then
initiate systemic inflammatory response syndrome (SIRS), LOS, NEC, and multisystem organ
failure. Native gut microbes are an important source of maturation signals to the infant's
developing immune system. Promoting the development of a healthy microbiota in preterm
infants is important in preventing NEC and LOS , but the key question is whether natural
colonization and succession of microbiota is possible in these infants.
Probiotics are defined as live microorganisms that benefit the host and are often
administered enterally to colonize the gastrointestinal tract. Preterm infants are at risk
for alterations in the normal protective microbiome due to increased rates of cesarean
delivery, exposure to antibiotics, exposure to hospital-acquired pathogens, lack of skin
contact with maternal flora, as well as conditions that preclude exposure to breast milk.
Modifications of the neonatal microbiome can have long-term effects on health that can last
into adulthood. Probiotics are used for various purposes, including preventing NEC and LOS in
newborns and infants, reducing the risk of infectious and atopic diseases and treatment
duration.
Multiple systematic reviews, meta-analyses, and network meta-analyses examining the results
of randomized controlled trials involving more than 10,000 preterm infants have shown
significant reductions in NEC and death with probiotic supplementation. When the literature
is examined, there are many studies examining prophylactic probiotic supplementation.
However, these studies were conducted by giving probiotics directly to babies. Although
routine prophylactic probiotic supplementation in preterm infants is controversial, the
safety of probiotic supplements is an important issue that should be emphasized. Although
there are studies reporting neonatal lactobacillus sepsis,caution is recommended before using
probiotics for prophylaxis in immunocompromised patients such as preterms.
Although there are many studies and meta-analyses on the use of probiotics in preterm
infants, the purity and numbers of live organisms in the products used, reports of probiotic
sepsis and contaminated probiotic products, and the lack of evidence regarding the optimal
probiotic strain and dose as well as the methodological differences in these studies. and
deficiencies have generated controversy and caused many neonatologists to avoid routine
probiotic administration. In many countries, probiotic products are introduced to the market
by bypassing the rigor of a drug's approval process in terms of safety, effectiveness, and
manufacturing standards and are generally available for use in the dietary supplements
category. As a result, currently available probiotics have not undergone drug approval steps
and cannot be marketed to treat or prevent diseases in preterm infants, including NEC and
LOS. If a probiotic is to be marketed as a drug for the treatment of a disease or disorder,
it must meet more stringent requirements, including evidence of safety, efficacy, and
approval as a drug for its intended use through clinical trials. The 2010 Clinical Report of
the American Academy of Pediatrics, written by the Committee on Nutrition, states that there
is insufficient data to recommend probiotics in very low birth weight infants, and because
not all probiotics have been studied, not all of them can be generally recommended. The
European Committee on Pediatric Gastroenterology, Hepatology and Nutrition recommends caution
in administering potentially infectious agents to VLBW babies due to their immunological
immaturity, but also states that there is insufficient data to conclude that probiotic
administration to preterm newborns is safe. Safety concerns regarding direct administration
of probiotics to preterm infants and evidence showing that probiotics given to preterm
infants reduce NEC and mortality, support a normal microbiome. has increased interest in
alternative methods for safe stimulation. Since it is known that maternal flora and breast
milk bacteria are naturally transmitted to fetuses and newborns, an alternative probiotic
exposure method that does not directly apply to preterm babies and therefore eliminates the
risk of transmission of possible contaminants is the administration of probiotics to mothers
of preterm babies.Consumption of breast milk contributes greatly to the colonization of
newborn babies (Evidence level: 1 +, Recommendation level: A). Studies have shown that there
are more than 200 bacterial species in breast milk, with Lactobacillus and Bifidobacteria
predominating, in addition to Staphylococcus , Streptococcus , and Corynebacteria. There is
evidence that the neonatal gut microbiome reflects the bacteria found in breast milk and
maternal feces. According to the entero-mammary pathway theory, bacteria settle in the breast
milk ducts from the mother's gastrointestinal tract through active transport from the blood.
Dendritic cells in the maternal intestinal lumen are thought to capture bacteria and
transport them to the breast via the blood with the help of mononuclear cells.
Since the human gut has evolved to carry a microbiota, it uses this microbiota to guide
developmental cues and various functions. Therefore, shaping the microbiota through breast
milk may affect lifelong health. The reduced incidence of NEC and LOS in breast-fed preterm
infants is thought to be strictly related to changes in the microbiome. Deoxygenation of the
infant gut over time is critical for the acquisition of difficult anaerobes (Bifidobacteria,
Bacteroides, Clostridia) that are essential for the healthy function of the microbiome. It
has been hypothesized that facultative anaerobes may contribute to deoxygenation, but these
organisms are also dangerous to the host. However, how many facultative anaerobes are in the
infant intestine, how long they colonize, and how they attach to the infant intestine are
clearly regulated by the components of breast milk. Therefore, it seems more reasonable to
observe the results by giving probiotics to mothers. The exact mode of action of probiotics
is likely strain dependent and difficult to assess due to the overall complexity of the
microbiota and interaction with the immune system. In vitro and in vivo studies have shown
that Lactobacillus and Bifidobacterium protect the intestinal tract by reducing intestinal
permeability and improving intestinal epithelial resistance. exerts direct effects on
epithelial barrier function. In our study, mothers in the intervention group will be given 80
ml probiotic product support containing the Actiregularis (5×106 CFU\mL) (lactobacillus
bulgaricus, streptococcus thermophilus, lactococcus lactis and bifidobacterium lactis)
strain. Although there are a limited number of studies conducted abroad on this subject, as
far as we know, our project has a unique value as it is the first project in which stool
microbiota results were evaluated in preterm babies by giving probiotics to mothers both in
our country and abroad. It carries.
Indirect hyperbilirubinemia in preterm infants is a common phenomenon caused by high
bilirubin production due to limited conjugation. Delay in starting enteral feeding in preterm
babies, etc. These conditions limit intestinal flow and bacterial colonization, leading to
increased enterohepatic circulation of bilirubin. It has been shown that feeding preterm
babies supplemented with probiotics regulates gastrointestinal motility and reduces
enterohepatic circulation.There are studies showing that the effect of probiotics on the
course of hyperbilirubinemia is effective in shortening the duration of phototherapy Another
unique value of our project is that probiotic support will be given to mothers and the
duration of phototherapy in babies will be evaluated.
Extrauterine growth restriction at discharge is common in preterm infants and is associated
with slower growth rates during hospitalization, associated with significant calorie and
protein deficiencies and preterm complications.Therefore, optimizing nutrition for preterm
infants is among the priority goals. Another effect of probiotic supplementation to preterm
babies is a significant decrease in the time to reach full enteral feeding. Other benefits
include increased weight gain and reduced time to regain birth weight, shorter hospital stay
and fewer episodes of food intolerance, reduced time to transition from orogastric to
breastfeeding, and increased postprandial mesenteric flow. In this project, other parameters
to be evaluated include the probiotic given to mothers, the baby's weight gain, length of
hospital stay, and time to transition to oral feeding.
Breast milk and breastfeeding training will be given by the researcher who has received
breast milk and breastfeeding consultancy training in order to ensure that mothers give only
breast milk for 20 days, which is one of the criteria for achieving the outcome goals of this
project. The fact that breastfeeding consultancy will be provided within the scope of the
project is another unique value of the project in terms of protecting and improving
mother-child health due to regional characteristics (the province with the highest fertility
and child population).
As a result, with this project, the incidence of NEC and LOS in preterm babies due to the use
of probiotics added to maternal nutrition, as well as weight gain in babies, duration of
phototherapy, time to transition to oral nutrition and hospitalization times will be
evaluated. In many studies, probiotics were given to babies and the results were examined.
However, the adverse relationship between the safety concerns mentioned above and the current
benefits of probiotics leads to the search for a safer route of administration for preterm
babies. Although there are a limited number of studies on this subject, the unique value of
our project is that probiotic support will be provided to mothers of preterm babies.
Research Hypotheses There is a difference in the incidence of NEC between the intervention
and control groups.
There is a difference in the incidence of LOS between the intervention and control groups.
There is a difference between the intervention and control groups in terms of the duration of
phototherapy.
There is a difference between the intervention and control groups in terms of time to
transition to oral feeding.
There is a difference between the intervention and control groups in terms of growth (weight
and head circumference) indicators of babies.
There is a difference in length of hospital stay between the intervention and control groups.
