A Randomized Placebo Controlled Pilot Study of Probiotic Supplementation in At-risk Pregnant Women

Study Overview
=================
Brief Summary
-----------------
The goal of this randomized supplementation feasibility trial is to learn about the feasibility and preliminary efficacy of the probiotic, lactobacillus plantarum 299v (Lp299v), in pregnant individuals at-risk for iron deficiency anemia. The main questions it aims to answer are: Is daily oral Lp299v a feasible and tolerable intervention for pregnant individuals to uptake? Does daily oral Lp299v in pregnancy impact maternal and neonatal cord hematological and iron status parameters? Participants will be randomly assigned to one of two treatment groups: daily intake or probiotic Lp299v + prenatal vitamin with iron or placebo + prenatal vitamin with iron from 15-20 weeks of gestation through delivery. Researchers will compare the two treatment groups to see if there is a difference in the feasibility of the intervention and the preliminary efficacy on maternal and neonatal cord hematological and iron status parameters.

Detailed Description
-----------------
The most prevalent micronutrient deficiency in the United States (U.S.) is iron; a large majority of cases of iron deficiency (ID) and iron deficiency anemia (IDA) occur among pregnant women. During pregnancy, maternal iron stores are used for the growing fetus, maternal red blood cell (RBC) expansion, and placental growth and development, thus increasing the risk for ID and IDA. Across all trimesters of pregnancy in the U.S., it is estimated that 18% of individuals have ID and 5% have IDA, and within the third trimester, the prevalence of ID exceeds 27%. Prevalence of IDA is even greater among those who identify as Black or low-income. Maternal ID and IDA are associated with increased risk of preterm birth, low infant birth weight, maternal and fetal mortality, and irreversible infant neurocognitive defects. To meet this increasing requirement for iron and to optimize maternal iron nutrition, the Recommended Dietary Allowance for pregnancy is 27 mg/day of iron. However, given the continued high rates of maternal ID and IDA and only modest adherence to daily prenatal vitamins containing iron, alternative approaches to optimizing iron nutrition in pregnancy are needed. Research has shown that one-time or short-term dosing of the probiotic Lactobacillus plantarum 299v (Lp299v) enhances iron absorption in non-pregnant populations. However, few studies have examined the effect of long-term supplementation on body iron stores. While probiotics are considered safe to consume in pregnancy, only one Lp299v supplementation trial has been conducted during the gestational period to evaluate its effects on maternal iron stores and risk of IDA. This study, among iron-sufficient pregnant Swedish women, showed a significantly lower decline in iron stores and a significantly lower prevalence of IDA in the third trimester among those randomized to Lp299v compared to standard care control. These results offer potential positive effects for the role of Lp299v in maintaining maternal iron status among those starting pregnancy with sufficient iron stores and who receive care in a decentralized publicly funded healthcare system. However, no studies have evaluated the effect of Lp299v on maternal iron status among individuals at risk for IDA in pregnancy in the U.S., nor have studies extended findings to neonatal iron status. Moreover, it is unknown if positive feasibility and preliminary efficacy would persist in a U.S.-based health care setting with racially, ethnically, and socioeconomically diverse pregnant individuals. Therefore, the objectives of this study were as follows. First and foremost, we examined the feasibility of daily oral Lp299v maternal supplementation taken from the early second trimester through birth. Second, we explored the preliminary efficacy of Lp299v intake on maternal (at-risk for IDA defined as hemoglobin (Hb) between 10.0-12.0 g/dL) and neonatal cord hematological and iron status parameters compared to controls in an urban U.S. academic medical center with a racially, ethnically, and socioeconomically diverse patient population.

Official Title
-----------------
Pro-Moms - Mitigating the Effects of Structural Violence on Maternal Iron Status: a Randomized Placebo Controlled Pilot Study of Probiotic Supplementation in At-risk Pregnant Women

Conditions
-----------------
Iron-deficiency, Pregnancy, High Risk, Stress, Psychological

Intervention / Treatment
-----------------
* Dietary Supplement: Probiotic LP299v 10x10 colony forming units in capsule form
* Other: Placebo in capsule form


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: a 1st trimester hemoglobin (Hb) of 10.0 - 11.9 g/dl demonstrating ID or risk for prenatal ID singleton naturally conceived pregnancy < 20 weeks gestation 18 - 45 years of age sufficient fluency in English to complete study forms refrain from non-study dietary and pre-/probiotic supplements while enrolled in the study Exclusion Criteria: oral antibiotic use within the past 2 months autoimmune disease infection receiving steroid treatment bariatric surgery inflammatory bowel disease hyperemesis hematologic disorder (e.g., sickle cell disease) current tobacco use substance abuse in the last 6 months other chronic disorders such as type 2 diabetes

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotic LP299v<br>Women will receive 1 LP299v (10x10 colony forming units) in capsule form and 1 standard prenatal supplement in tablet form daily beginning at 15 weeks gestation through delivery. | Dietary Supplement: Probiotic LP299v 10x10 colony forming units in capsule form<br>* Daily lactobacillus plantarum (LP299v) 10x10 colony forming units in capsule form<br>|
| Placebo Comparator: Placebo<br>Women will receive 1 placebo in capsule form and 1 standard prenatal supplement in table form daily beginning at 15 weeks gestation through delivery. | Other: Placebo in capsule form<br>* Daily placebo in capsule form<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Adherence to the Supplement Regimen | Mean adherence to the supplement regimen using Pillsy smart bottles and standard pill counts. | 15 weeks gestation through delivery, an average of 25 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment-emergent Adverse Events Related to GI Symptoms | Adverse events were captured using the Maternal Adherence Form beginning with the first pill refill visit through delivery. number of participants reporting adverse GI events | 15 weeks gestation through delivery, an average of 25 weeks | 
| Maternal Hemoglobin | change in mean maternal serum hemoglobin (g/dl) from baseline to delivery | Assessed at baseline (i.e., 15-20 weeks gestation) through delivery; mean change from baseline to delivery is reported. | 
| Maternal Hematocrit | Change in mean maternal serum hematocrit (%) from baseline to delivery | Assessed at baseline (i.e., 15-20 weeks gestation) through delivery; mean change from baseline to delivery is reported. | 
| Maternal Iron | change in mean maternal serum iron (µg/dL) from baseline to delivery | Assessed at baseline (i.e., 15-20 weeks gestation) through delivery; mean change from baseline to delivery is reported. | 
| Maternal Total Iron Binding Capacity | change in mean maternal total iron binding capacity (µmol/L) from baseline to delivery | Assessed at baseline (i.e., 15-20 weeks gestation) through delivery; mean change from baseline to delivery is reported. | 
| Maternal Serum Ferritin | change in mean maternal serum ferritin (ng/mL) from baseline to delivery | Assessed at baseline (i.e., 15-20 weeks gestation) through delivery; mean change from baseline to delivery is reported. | 
| Maternal Transferrin Saturation | change in mean maternal transferrin saturation (%) from baseline to delivery | Assessed at baseline (i.e., 15-20 weeks gestation) through delivery; mean change from baseline to delivery is reported. | 
| Maternal High-sensitivity C-reactive Protein (Hs-CRP) | change in mean maternal high-sensitivity C-reactive protein (hs-CRP) (mg/L) from baseline to delivery | Assessed at baseline (i.e., 15-20 weeks gestation) through delivery; mean change from baseline to delivery is reported. | 
| Maternal Iron Deficiency Anemia | Number of participants who had iron deficiency anemia (IDA) at delivery. Hemoglobin, obtained from the Complete Blood Count, was used to define trimester-specific maternal IDA, with a downward correction of 0.8 g/dL for Black women. At the time of the study, it was recommended to use a race-adjusted cut-point for IDA. However, this race-adjusted cut-point was recently determined to be unfounded. IDA ranges included hemoglobin ≤11 g/dL for the first trimester, ≤10.5 g/dL for the second trimester, and ≤11 g/dL for the third trimester. IDA ranges with the correction for Black women were hemoglobin ≤10.2 g/dL for the first trimester, ≤9.7 g/dL for the second trimester, and ≤10.2 g/dL for the third trimester. | Assessed at baseline (i.e., 15-20 weeks gestation) through delivery; mean change from baseline to delivery is reported. | 
| Infant Hemoglobin | Mean infant serum hemoglobin (g/dl) from cord blood at delivery. | delivery | 
| Infant Hematocrit | Mean infant serum hematocrit (%) from cord blood at delivery. | delivery | 
| Infant Iron | Mean infant serum iron (µg/dL) from cord blood at delivery. | delivery | 
| Infant Total Iron Binding Capacity | Mean infant total iron binding capacity (µmol/L) from cord blood at delivery. | delivery | 
| Infant Serum Ferritin | Mean infant serum ferritin (ng/mL) from cord blood at delivery. | delivery | 
| Infant Transferrin Saturation | Mean infant transferrin saturation (%) from cord blood at delivery. | delivery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pregnancy, iron status, structural violence