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ORIGINAL ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 3  |  Page : 126-133

Effect of Probiotic Supplementation on Glycemic Control Among GDM − Study Protocol for a Randomized Clinical Trial


1 Sri Ramachandra Faculty of Nursing, Sri Ramachandra Institute of Higher Education and Research (DU), Porur, Chennai, Tamil Nadu, India
2 Department of Obstetrics and Gynaecology, Sri Ramachandra Medical Centre & Hospital, SRIHER (DU), Porur, Chennai, Tamil Nadu, India
3 Omayal Achi College of Nursing, Puzhal, Chennai, Tamil Nadu, India

Date of Submission21-Feb-2022
Date of Decision15-Apr-2022
Date of Acceptance19-Apr-2022
Date of Web Publication3-Oct-2022

Correspondence Address:
Nalini Sirala Jagadeesh
Sri Ramachandra Faculty of Nursing, Sri Ramachandra Institute of Higher Education and Research (DU), Porur, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnpnd.ijnpnd_8_22

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   Abstract 


Background: Diabetes is the ninth leading cause of death among women globally causing 2.1 million deaths per year. Pregnancy complicated with gestational diabetes mellitus (GDM) causes physiological resistance to insulin that predisposes to maternal (pregnancy-induced hypertension, macrosomia, and obstructed labor due to shoulder dystocia) and fetal (macrosomia, birth injuries, hypoglycemia, respiratory distress) complications associated with the GDM. Given the complications associated with GDM in South India, the study hypothesized that a novel idea of probiotics supplementation as adjunct therapy with comprehensive intervention would show considerable improvement in maternal glycemic control among GDM. Methods/Design: It is a single-center, double-blind randomized controlled trial. Study population: Expectant women with GDM in their second trimester were randomized to control and intervention group. Intervention: The package included supplementation with probiotics (probiotic capsules with routine care), while the control group: received a placebo capsule (placebo capsule with routine care) to GDM women. The study participants were followed up till delivery. Outcome measures: Maternal blood glucose levels as fasting and postprandial blood glucose levels are measured at the 20th, 32nd, and 40th weeks of gestational age. Secondary outcome measures: Maternal parameters are monitored at their regular follow-up visits, and neonatal parameters are measured after delivery. Statistical analysis: Descriptive and inferential analyses were performed that satisfied the per protocol compliance using the recent version of Statistical Package for the Social Sciences. Conclusion: Probiotic supplementation is one of the emerging trends that shows a significant impact on maternal blood glucose levels, which will in turn have beneficial effects on maternal and neonatal morbidity and mortality. In a developing country like India, with the growing burden of diabetes and GDM, developing an innovative effective intervention that promotes glycemic health that can easily be replicated across various settings will become a priority. If the intervention is concluded to be effective, this study would become a guideline model to reinforce probiotics as an intervention to treat GDM and contribute to improved maternal and neonatal health in South India.

Keywords: Blood glucose levels, diabetic diet, gestational diabetes mellitus, glycemic levels, physical activity, probiotics


How to cite this article:
Ramanathan K, Jagadeesh NS, Vishwanath U, Dayal C. Effect of Probiotic Supplementation on Glycemic Control Among GDM − Study Protocol for a Randomized Clinical Trial. Int J Nutr Pharmacol Neurol Dis 2022;12:126-33

How to cite this URL:
Ramanathan K, Jagadeesh NS, Vishwanath U, Dayal C. Effect of Probiotic Supplementation on Glycemic Control Among GDM − Study Protocol for a Randomized Clinical Trial. Int J Nutr Pharmacol Neurol Dis [serial online] 2022 [cited 2022 Dec 6];12:126-33. Available from: https://www.ijnpnd.com/text.asp?2022/12/3/126/357223




   Introduction Top


The International Diabetes Federation (IDF) had estimated that the global prevalence of diabetes mellitus has been increasing as mentioned against the years: 2000, 2003, 2006, 2009, 2011, 2013, and 2015 as 151, 194, 246, 285, 366, 382, and 415 million, respectively. A recently published paper by IDF highlights that the global burden of diabetes that was estimated at 451 million in 2017 is expected to rise to 700 million by 2045.[1] The crude prevalence of gestational diabetes mellitus (GDM) ranges from 3.81% in 2006 to 6.53% in 2015, almost doubling in a decade (P < 0.001).[2]

The overall prevalence of GDM in Chennai showed an upward trend from 13.4%.[3] to 18.5% with no significant differences in the urban versus rural areas (urban 19.8% vs. rural 16.1%, P = 0.46). In a pregnancy complicated with GDM, there will be an increase in insulin resistance as the pregnancy proceeds. This resistance is aggravated by many factors such as an increase in the secretion of pregnancy hormones, namely, human placental lactogen, estrogen, progesterone, cortisol, and prolactin. Hence, the GDM sets in a normal pregnancy when the insulin secretion could not overcome this physiologic insulin resistance leading to the development of increased blood glucose levels.[4]

Clinically, the GDM is treated using medical nutrition therapy (MNT) with physical therapy. The possible combination of interventions are the dietary + exercise + medication + health education + psychological (DEMHP) interventions, which accounted for the highest percentage (27.4%) of these studies.[5]

The alternative strategies in the management of GDM need to be considered and trialed in combination with the dietary and exercise interventions.[5] Gut microbiota and its pathomechanism on diabetes is an emerging trend in the management of metabolic diseases.[6]

The term “gut microbiota” is referred to as the colonization of the microorganisms in the human gastrointestinal tract. In simple, these are termed good bacteria that exert anti-inflammatory action on the host and play a key role in energy metabolism and hence confer a symbiotic relationship with the host.[7],[8],[9] The imbalance between the above said commensal symbionts and pathobionts is referred to as dysbiosis.[10]

This disparity in the gut microbiota leads to the development of dysbiosis in pregnant women. It is identified, Modify as Evidence proclaimed that dysbiosis was observed in pregnant women and reported to have a high association with changes in metabolic hormones and blood glucose levels.[11] Therefore, the above literature collectively gave the researcher a novel idea of altering the composition of gut microbiota by using “good bacteria” or otherwise termed “probiotics” might yield a promising outcome by improving the glycemic and the outcomes of pregnancy among women with the GDM.

To the best of our knowledge, this is the first of its kind to be trialed out in South India and this region has not got any previous studies investigating the effectiveness of probiotic supplementation on glycemic control among women with GDM in Chennai, South India. Should this trial prove to be effective, this could be used as a guideline framework for this model of intervention and could replicate in any other setting in South India, be it rural or urban.


   Methods/Design Top


It is a randomized controlled trial, a prospective double-blinded placebo-controlled clinical trial with parallel arms that investigated whether maternal probiotic supplementation affected the maternal glycemic biomarkers among women with GDM, in Chennai, India. This study design followed a true experimental design and will report the results following the CONSORT 2010 statement-reporting guidelines for parallel group randomized trials.[12]

Manipulation: It is the intervention that was given to the participants assigned to the experimental group. In this study, a package of interventions supplemented with probiotics (a capsule of probiotics with the routine care of GDM) was the intervention given to the experimental group.

Package of interventions supplemented with probiotics: This was a comprehensive package of interventions designed to improve the maternal blood glucose levels and to identify its impact on the outcomes of pregnancy in terms of the maternal and the neonatal outcomes. This package comprised capsules of probiotics as supplementation with the modifications of the diet and the physical activity.

Probiotics: This supplementation of the capsule is a commercially available product manufactured with two subspecies or strains of Lactobacillus, namely, L. rhamnosus and L. reuteri, of dose 1 billion colonies forming a unit of each subspecies. This was given as a supplementation to the participants in the experimental group starting from the day of assignment into the study group until the delivery of the baby.

Physical activity: It refers to the freestyle walking daily for at least 30 minutes/day or 180 minutes/week. It was measured in terms of the number of footsteps by using a pedometer worn by the study participants at the time of walking. This intervention commenced from the day of enrollment into the 20 to 24 weeks of gestational age (GA). However, the daily step counts are recorded for 7 consecutive days in a week and at the gestation of 33 to 36 weeks and 37 to 40 weeks before the delivery.

Diet: The study participants will be educated on the modifications of diet to be followed during the pregnancy by a registered dietitian. After the counseling on diet, the researcher will ask the study participants to record their dietary intake for 3 nonconsecutive days (two weekdays and at the weekend). The researcher will reinforce to comply with the given diet restrictions during every follow-up visit of the study participants. The compliance to the diet will be measured at 20 to 24 (baseline), at the GA of 33 to 36 (posttest I), and at 37 to 40 weeks of GA (posttest II).

Control group: This helped to create a comparable group from the same environment to compare the outcomes objectively. In this study, the control group was identified from the same environment and supplied the placebo capsule in the place of probiotics. Placebo is a capsule that was given to the control group from the time of enrollment into the study until the delivery. This capsule is commercially manufactured by using microcrystalline cellulose.

Both experimental and control groups received reinforcement to consume the capsules every day during their scheduled visit for antenatal follow-up. The participants got reminder messages to consume the capsules every day from the onset of enrollment into the study until the delivery. The pill count was done by an individual, who was not involved in the study, as a measure of compliance to identify if any capsules are left out. The researcher measured the compliance to the consumption of capsules every month on the day of the participants’ scheduled visit for follow-up.

Randomization: In this study, stratified randomization was followed and assessed all the target population for satisfying the eligibility criteria and assigned to either the experimental or the control group following the stratified randomization.

Randomization procedure: The following steps were followed for the randomization of the study participants:
  1. In this study, the blood glucose level of the women with GDM is considered as the variant that might affect the outcome of the intervention as the range of blood glucose levels extends from 140 >199 mg/dL. Thus, to have a homogeneous number of participants in both the groups, the investigator planned to stratify the elevated blood glucose levels into three strata, namely, >140 to 169 mg/dL, >169 to 199 mg/dL, and >199 mg/dL. This was finalized after the feasibility test to only two strata, namely, >140 to 169 mg/dL and >169 to 199 mg/dL, due to constraints faced by the investigator during the feasibility study.
  2. The patients who satisfied the predefined criteria were assigned to each of their respective strata, that is, >140 to 169 mg/dL and >169 to 199 mg/dL.
  3. After assigning the participants to their respective stratum, following simple randomization on a 1:1 basis, they were allocated to the experimental and the control group. This simple randomization sequence was generated by using computer-based random number generators (simple randomizer/V1/lists).


Measures that will be considered to avoid bias: Bias is a systematic error that can distort the validity of the study findings. It happens during the research process,[13],[14] particularly during the conceptualization or conduction of a research process. Such type of bias could be prevented by using blinding or masking in the trials, in which the treatment or intervention given for a particular condition was not revealed to the individuals who received the care in the trial. In this trial, the capsules (probiotics and placebo) that were supplemented as an intervention were blinded. The procured capsules were given to the pharmacy lab in charge under the Faculty of Pharmacy in the selected study setting in Chennai. The lab in charge concerned blindfolded both the probiotics and the placebo containers. That hold the name of the capsules (combination of probiotics and dosage) with a label named Group A and B. The capsules were held in the pharmacy lab, carefully stored in a lock and key cupboard, and maintained under their strict supervision. The investigator, participants, and other outcome assessors were not aware of the intervention group (recall, performance, and detection bias, respectively). Thus, this study followed triple blinding to prevent the bias of placebo, performance, and detection carefully.

Independent variable: In this study, a package of interventions supplemented with probiotics is the independent variable.

Dependent variables: This study measured the maternal glycemic level and the pregnancy outcomes as dependent or outcome variables.

Primary outcome variables: Here, the fasting and the postprandial blood glucose levels of the study participants were measured as the (glycemic level) primary outcome variables.

Secondary outcome variables: The pregnancy outcomes of the study participants are regarded as the secondary outcomes that were measured in terms of the maternal and neonatal outcome variables.

Maternal outcome variables: The variables such as maternal weight gain, mode of delivery, GA of delivery, duration of labor, and comorbidities in pregnancy were measured from the study participants as the maternal variables.

Neonatal outcome variables: The variables birth weight, Apgar score, shoulder dystocia, and admission into Neonatal Intensive Care Unit (NICU) were noted as the neonatal variables.

Setting

The study participants were recruited from the antenatal outpatient and inpatient department under Obstetrics and Gynaecology (OG) Department of a Tertiary Care Centre in Chennai. This is a nationally recognized multispecialty tertiary health care center located in Chennai, the capital city of Tamil Nadu. It acts as a center of excellence in catering services to the middle and the lower middle-class groups of clientele that are residing in and around Porur.

Population

Target population: The target population of this study was all the pregnant women who were diagnosed with GDM and attending the antenatal outpatient department (OPD) to receive the focused antenatal care for GDM.

Accessible population: The accessible population of this study were all pregnant women who were diagnosed with GDM and attended the antenatal OPD of the study setting for the focused antenatal care for GDM.

Sampling process

Sample: The pregnant women with GDM attending the antenatal OPD for the focused GDM care in the study setting and satisfying the predefined inclusion criteria of the study were regarded as the study samples.

Sample size and statistics

Considering the mean difference of 8 in the fasting blood glucose levels, and the population variance (d2) of 6, based on the previous literature,[15] the sample size was calculated with the power of the study as 90% at 5% significance level with a two-sided test by using the sample size formula:

N = (Zα/2+Zβ)2 *2*σ2/d2

Reliability coefficient at that level (Zα/2) = 1.96

The desired power of the study (Zβ=90 %) = 1.28

The estimated variance from the previous study (σ2) = 8

Significance level (α)  = 5%

Population variance (d2) = 6

The estimated sample size was 76 subjects together for the intervention and the control groups (38 in each). The final calculated sample size (N) (after oversampling with a 20% attrition rate) was N = 92, that was approximated to 46 each in the intervention and control group.

Sampling technique

In this study, a consecutive sampling technique was used. In this technique, the researcher chose the subjects to be part of the study with a specific objective and fulfilling the predefined inclusion and exclusion criteria of the study.

Sampling criteria

Inclusion criteria

Pregnant women with GDM:
  • Singleton pregnancy
  • Primi- and multigravidae
  • Normal ultrasound scan of the fetus at the GA of 12 to 14 weeks
  • The GDM between the GA of 20 and 24 weeks screened by the consultants of the Obstetrics and Gynaecology Department (OG) of the study setting


Exclusion criteria

Pregnant women diagnosed with GDM:
  • At the GA >24 weeks at the time of recruitment for the study
  • Pregestational diabetes
  • Consume medications influencing insulin resistance (glucocorticoids and immunosuppressants)
  • Had taken any form of commercially prepared foods or medications supplemented with probiotics <1 month before the inclusion.


Data collection instruments

The researcher to the best of her knowledge carried out a thorough search of the existing literature and discussed it with the research advisory committee members prior to the preparation of the tool. Based on the expert guidance and the prevailing literature, the following instruments were developed to gather the necessary data required to answer the research questions of the present study.

Part I: Background variables

Section A: Demographic data

Section B: Clinical data

Part II: Outcome variables

Section A: Biochemical variables

Section B: Maternal variables

Section C: Neonatal variables

Section D: Compliance measurements

Part I: Background variables: It consisted of two sections. Section A dealt with demographic data and Section B the clinical data.

Section A: Demographic data: This section pooled the data related to study participants’ age (in years), educational status, occupation, type of family, the income of the family, and place of residence.

Section B: Clinical data: This consisted of items related to the family history of diabetes mellitus and gravida of the study participants.

Content validity

Sections A and B

Demographic and clinical data: Sections A and B of Part I of the data collection tool along with the background information of the present study together with the research objectives and the checklist of the validation of the tool were given to 11 experts from the fields of obstetrics and OG nursing (six), pediatrics and child health nursing (two), and microbiologist (three). The experts were requested to give their valuable opinions and suggestions based on the relevancy, accuracy, and appropriateness of the tool. The content validity index was calculated and expressed as the coefficient of validity index.

Language validity: The Section A of Part I was translated into the local language by the language experts. The retranslation into English was done to check the language validity by another expert.

Part II: Outcome variables

It consisted of four sections A, B, C, and D with all the items the researcher had developed. The areas included the following.

Section A: Biochemical variables

This part included a table that intended to record the glycemic control levels of the pregnant women with GDM, measured in terms of fasting and the postprandial (2-hour post meal) blood glucose levels in mg/dL.

Section A: Assessment of biochemical variables as primary outcomes

Maternal fasting and postprandial blood sugar are the primary outcomes of this study. These were measured at the Gestational Age (GA) of 20 to 24 weeks (baseline), 33 to 36 weeks, (posttest I), and after the delivery (posttest II). This test included 10- to 12-hour pretest fasting. The fasting blood samples were (2 ml each for six times) collected from the forearm vein by a trained laboratory technician in the study center for measuring the fasting blood glucose at the study settings central laboratory at 20 to 24 weeks GA (baseline), 33 to 36 weeks GA (posttest I), and 37 to 40 weeks of GA (posttest II) visits. The plasma glucose levels were assessed using a glucose oxidase and peroxidase (GOD-POD) methodology. Any pregnant woman undergoing the above test who reported with a postprandial venous plasma glucose cutoff ≥140 mg/dL was classified as having GDM. The above diagnostic criteria were followed in this study as advised by the specialist consultants of the Department of Obstetrics and Gynaecology and are the standard protocol followed in the study settings. This is considered a more convenient and acceptable method in the developing countries especially in the Indian scenario as the Indian women in the South Asian countries showed the highest prevalence of GDM (Rani et al., 2016).[16] Similarly, a large community-based cross-sectional survey to determine the prevalence of GDM in the urban, the semi-urban, and the rural levels used the diagnostic criteria recommended by WHO that recommended a 2-hour 75 g post-glucose value ≥140 mg/dL.[3]

Section B: Maternal variables

It consisted of items related to the study participants’ height, weight, mode of delivery, GA of delivery, and comorbidities of pregnancy such as pregnancy-induced hypertension and preeclampsia.

Section B: Assessment of maternal variables (height and weight)

Calibration of the instruments: The instruments measured the study participant’s height and weight under Section B (height and weighing scale) calibrated at the biomedical services of the study settings in Chennai.

Section C: Neonatal variables

This part included items that will be related to neonates’ birth weight, Apgar score, shoulder dystocia, and admission to NICU.

Section C: Birth weight

Calibration of the instrument: The weighing scale was used for assessing birth weight that was calibrated at the biomedical services, of the study settings, in Chennai.

The data in the above sections (Sections A, B, and C) are the factual information gathered from the records of study participants. Hence, these data did not necessitate any scoring and interpretation of the dataset.

Section D: This part consisted of items that recorded the compliance of the following:

  1. The capsules of probiotics/placebo: Measured in terms of the number of pills consumed and the pills left out
  2. Physical activity: In terms of number of steps/days
  3. Pertaining to dietary practices: This part of pooled data related to the dietary practices followed by the study participant for two weekdays and one weekend as a 3-day diet record. The study participant recorded this as food consumption − morning meal, midmorning snacks, lunch meal, evening snacks, and dinner


Content validity

To establish the content validity, the above tool was submitted to 11 experts from the fields of OG nursing, child health nursing, community health nursing, and medical surgical nursing.

Ethical considerations

Administrative permission: Due permission was obtained from the Medical Superintendent, the Head of the Department of Obstetrics and Gynaecology, of the study hospital to commence the trial.

Ethical clearance: The Institutional Ethics Committee (IEC) of the study settings approved the study (IEC/18/APR/140/10).

Trial registration: The present study was registered in the Clinical Trial Registry of India (CTRI) and the trial registration number is CTRI/2018/08/015432.

Informed consent: A detailed subject information sheet was administered in the local language to all the participants. This sheet included comprehensive details about the research study, explained their involvement, benefits and risk (moderate) involved in the study, and whom to contact in case they had any doubt with regards to the study to each study participant clearly prior to the study.

Data collection procedure: The study was conducted from June 2019 to March 2020. A formal written permission for conducting the study was obtained from the Medical Superintendent and the Head of the Department of Obstetrics and Gynaecology at Sri Ramachandra Hospital, Chennai. Ethical approval for the study was sought from the Institutional Ethical Committee, of the parental hospital and registered to the CTRI prior to the commencement of the study.

The pregnant women who were diagnosed with GDM and reported to antenatal OPD in the study settings were considered the target population and selected those who satisfied the inclusion criteria of the study as the samples. The entry of first study participant into the experimental and control group was in June.

The consented participants were randomized following stratified randomization. The stratifications, identified based on the report of the pilot study of the current trial, were done for the postprandial blood glucose levels as >140 to 169 mg/dL (strata 1) and >169 to 199 mg/dL. Based on the stratifications, mentioned above, the women with GDM were identified and assigned to Group A and B on a 1:1 basis by following simple randomization (list) that was generated by using randomizer/lists/V1 a computer software. The study participants were blinded to the details of the intervention and control groups.

After the random allocation, the study participants’ background variables were assessed using Part I of the data collection tool by self-report. Section A, Section B were used to measure, FBS and PPBS levels, maternal height, and weight, respectively as the baseline measures at 20–24 weeks of gestational age (GA). They were directed to receive counseling on diet from the trained dieticians in the same setting. After the counseling on diet, the investigator met the study participants and explained the modifications of diet, the physical activity (walking), and the supplementation of probiotic capsules as a package of interventions for managing the GDM. They were explained on the interventional package that they would receive during the study period. The participants were given time to clarify the importance of diet, physical activity, and supplementation of probiotics in the management of GDM. After the clarifications, if any, the researcher administered the capsules of probiotics/placebo to the study participants concerned based on the groups allocated to them. That is, the study participants who were allocated to Group A received a capsule container labeled as Group A, while those allocated to Group B had a capsule container labeled as Group B. The study participants were not aware of the details of the intervention or control group. They were explained on the package of interventions and collected the data follows:

Probiotics capsules: After the assignment into the groups, the study participants were instructed to take one capsule a day, and each container had 30 capsules for 30 days. Further, they were reiterated that the capsules would be supplied until their delivery of the baby as a monthly supplementation, during their scheduled antenatal follow-up visit of 4 weeks’ interval and issue the next container only upon returning the old container/unused capsules during their next follow-up visits. The researcher marked the scheduled follow-up visit dates of each study participant along with the contact number. The telephonic reminder messages were sent daily to the study participants to consume their capsules. Thereafter, they were advised to meet the researcher in room number 9 in the antenatal OPD with the capsule container during their scheduled follow-up visits of 4 weeks’ interval. At every 4-weekly follow-up visit, the study participants met the researcher in the room number 9 and exchanged the old capsule container with the new one with 30 capsules of supplementation. The graduate nurse, who was unconnected to the study and belonged to the antenatal OPD, measured the pill count of the container returned for the unused capsules. Likewise, the repeat follow-up measurement of the pill count was done at every 4-week interval to assess the compliance of the capsules and it was recorded in the tool of Section D, Part II.

For the physical activity, the study participants were informed about the pedometer that was used for assessing their daily physical activity (walking) in terms of footsteps. The researcher downloaded the app recommended by the manufacturer to the mobile phone and asked the study participants to wear it on their wrists during walking. The pedometer was connected to the downloaded mobile app, which recorded the number of footsteps automatically. The women wore the pedometer for 7 consecutive days at the GA of 33 to 36 weeks (posttest I) and 37 to 40 (posttest II) weeks. After the posttest I and II the pedometer were collected from the study participant and downloaded the foot counts records through the app. The downloaded counts of footsteps were recorded in the table of physical activity compliance under Section D of the outcome variables.

Concerning the modifications of diet, the investigator reinforced on the diet modifications recommended during the counseling. They were firmly encouraged to comply with the diet and alerted that their compliance would be monitored through a 3-day diet record. The participants were instructed to record the details of food they consumed in a separate notebook for any 2 weekdays and 1 weekend day of a week after 4 weeks of their enrollment into the study and at the end of the study. They were asked to record the diet they consumed in terms of breakfast, midmorning snacks, lunch meals, evening snacks, and dinner meals in a notebook. The beverages consumed were also included as a part of the meals or snacks. This record of dietary practices of the study participants was collected at the GA of 20 to 24 weeks on the enrollment day. Later, the study participants were asked to record their dietary practices after 4 weeks as a measure of posttest I. The repeat measurements were recorded at the end of the study as posttest II and noted in a 3-day diet record under Section D of the outcome variables, part II of the tool.

Follow-up visit measurements: All the study participants were encouraged to strictly adhere to the regular antenatal care focusing on the GDM as advised in the study setting. Among the women with GDM, the antenatal care was made more intensive to achieve the glycemic control that is as near to physiological level as possible during pregnancy. Hence, in this study setting, the target women with GDM were encouraged for the follow-up visits at 4 weeks’ interval until the GA of 28 weeks, while bimonthly interval follow up until GA of 36 weeks and weekly follow up until the delivery. Further, at times based on the needs of the women with GDM the AN visits were made biweekly to closely monitor the maternal blood glucose levels. Moreover, to stabilize the blood glucose levels and monitor the fetal growth, the target women were advised for inpatient care.

Therefore, based on the above focused antenatal visits for the GDM, the researcher who was blinded assessed the outcomes of the study participants.

Assessment at the follow-up visit (at the GA of 33–36 weeks): During this time, the posttest I, the FBS, and the PPBS (biochemical variables) as the primary outcomes and the secondary variables such as the maternal variables highlighted under Section B for all the study participants were measured. The compliance of the interventions monitored in Section D of Part II was also checked during this time.

Assessment at the follow-up visit (at the GA of 37–40 weeks): This follow-up visit aided the researcher to assess the posttest II at this time, measuring the FBS and the PPBS (biochemical variables) as the primary outcomes and the secondary variables such as the maternal variables highlighted under Section B for all the study participants. The compliance of the study participants to the interventions monitored in Section D of Part II was also checked during this time.

Assessment after delivery: At this point in time, the secondary variables, namely, neonatal variables, highlighted under Section C, were measured for all the study participants.

During their scheduled follow-up visit, the researcher had a talk on reinforcement during the mothers’ meeting at the antenatal OPD and ward and answered the queries in person during their follow-up visit and telephonically during their clarification call. The primary and the secondary outcomes were measured at the stipulated assessment scheduled as mentioned above. The investigator kept following the enrolled study participants until the GA of 37 to 40 weeks and discussed their delivery plan with the staff nurses in the study setting during the third trimester of the women with GDM.

The researcher kept connected and followed up with the women with GDM until the delivery through the telephonic reminders. After the delivery, a reinforcement session was held with all the participants concerning the continuation of the modifications of diet and the physical activity. The outcome data were collected from the mothers on maternal weight after delivery, maternal variables such as mode of delivery, GA, blood glucose levels, and neonatal variables such as birth weight, Apgar score, shoulder dystocia, neonatal admission to ICU, and the investigator, who was blinded, observed the reasons for the NICU admission. At the end of the study, the investigator thanked all the mothers and their family members for their kind cooperation. Moreover, the researcher ensured her availability on the same telephone number and asked them to contact her for further help at any time without hesitation irrespective of their completion of the study period and shared the telephone number with the target population who visited the research setting for the focused GDM care.

Plan for data analysis: The data obtained were coded and planned to use the Statistical Package for the Social Sciences version 20 for analyzing the data. The analysis process is going on. Based on the objectives of the study and to test the hypothesis, it was planned to use descriptive and inferential statistics.

Descriptive statistics such as frequency, percentage, mean, and standard deviation will be used to assess the demographic and the clinical data.

Inferential statistics: Independent t test were carried out to test the homogeneity of baseline outcomes variable among the probiotics and placebo groups. The same test is used to determine the mean differences in blood glucose levels (FBS, PPBS) of the pregnant women between the intervention and control groups. The paired t test will be used to find the mean differences in the blood glucose values (FBS, PPBS) among the pregnant women within the probiotics and placebo groups.

Testing the hypothesis

The hypotheses of the present study were tested by using repeated measures of “ANOVA” to determine the effects of the supplementation of probiotics on the outcome measures such as glycemic control (FBS, PPBS) and pregnancy outcomes (maternal and neonatal variables) that were measured at different points of time. Therefore, to find out whether there was a statistically significant difference, repeated measures of ANOVA will be computed. The RM-ANOVA was used with Mauchyl test to check the assumption of sphericity violation (P < 0.05).

Furthermore, the difference in the outcome variables (FBS, PPBS) collected at different points of time were assessed by post-hoc test that was computed using the Bonferroni correction and compared the differences between intervention and control group.


   Discussion Top


This study protocol intended to determine the effects of probiotics supplementation as a novel intervention for expectant women with GDM in South India. The researcher expected that the projected adjunct therapy (probiotics) as intervention and its effect in reducing the glycemic biomarkers among GDM women as the study addressed the all previously identified contributing factors for noncompliance to the adjunct therapy, namely, forgetfulness to take the new medications, irregular follow-up, and lack of reminder messages. We the researchers believed that this unique comprehensive therapeutic approach is the foremost strength of our study. Additional strengths of this study included a double blinding controlled trial that has not been tried in the previous trials in India.

Despite the above strengths, this study also faced some limitations. The first limitation was the sampling frame, which included expectant GDM at the GA of 20 weeks rather than the first trimester population of expectant mothers. These population criteria were considered as the diagnosis of GDM that was confirmed only at 20 to 24 weeks of GA as per WHO diagnostic criteria. However, this limitation was unlikely to affect the main outcome of the study.


   Conclusion Top


The proposed intervention, if it concludes to be effective, the outcome might show considerable impact on the maternal and neonatal morbidity and mortality rate. Further, the study is projected to produce worthwhile data that will boost to replicate the proposed model of intervention in South India and other developing countries. This study highlighted the cumulative effect of using adjunct therapy as a means to manage expectant GDM to regularize glycemic biomarkers.

Acknowledgment

We are grateful to the nursing staff and health care team members of study settings for their valuable help while conducting data collection for the pilot and the major study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
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