RCT of Prenatal Choline Supplementation During Pregnancy to Mitigate Adverse Effects of Prenatal Alcohol Exposure

A Randomized, Double-Blind, Placebo-controlled Clinical Trial of Choline Supplementation During Pregnancy to Mitigate Adverse Effects of Prenatal Alcohol Exposure on Growth and Cognitive Development

Although the adverse effects associated with prenatal alcohol exposure (PAE) are well known, many women continue to drink heavily during pregnancy, putting their infants at risk for fetal alcohol spectrum disorders. Animal studies have shown that choline supplementation can mitigate effects of PAE on growth and development. Choline, an essential nutrient, serves as a methyl-group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. In an R21 feasibility trial, 70 heavy drinkers were randomly assigned to receive a daily dose of 2g of choline or a placebo from initiation of antenatal care to delivery in Cape Town, South Africa, where the incidence of heavy drinking during pregnancy and fetal alcohol syndrome are among the highest in the world. When compared with infants in the placebo arm, infants in the choline-treated arm were more likely to meet criterion for eyeblink conditioning, demonstrated markedly better recognition memory on the Fagan Test of Infant Intelligence, which is known to have predictive validity for school-age IQ, and had better postnatal gains in weight and head circumference. Key features of this study included the higher choline dose (4.4 times adequate intake (AI), compared to 1.7-2.5 in previous human studies) and initiation of treatment early in pregnancy. We are now conducting a fully-powered, double-blind, randomized, placebo-controlled choline supplementation trial in heavy drinking pregnant women from a rural community in South Africa (1) to assess the effectiveness of maternal choline supplementation during pregnancy to mitigate effects of PAE on three primary outcomes: infant recognition memory and postnatal growth restriction (weight and head circumference); (2) to assess the efficacy of this supplementation for mitigating alcohol effects on the following secondary outcomes: infant eyeblink conditioning, postnatal length, and information processing speed; (3) to use innovative methods in causal inference analysis to examine protocol adherence as an important source of variation in treatment efficacy and to identify sociodemographic factors associated with non-compliance in order to facilitate implementation of the intervention protocol in clinical settings; and (4) in exploratory analyses, to examine whether maternal choline supplementation is particularly effective in women with lower dietary choline intake or poor nutritional status.

Study Overview

• Status: Recruiting
• Conditions: Fetal Alcohol Spectrum Disorders; Fetal Alcohol Syndrome
• Intervention / Treatment: Dietary supplement: Choline bitartrate; Dietary supplement: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 288
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: R. Colin Carter, MD, MMSc; Phone Number: +16176949902; Email: rcc2142@cumc.columbia.edu
• Study Contact Backup: Name: Sandra W Jacobson, PhD; Phone Number: +13139935454; Email: sandra.jacobson@wayne.edu

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • Recruiting
      • University of Cape Town Faculty of Health Sciences
      • Contact: Anthea Van Wyk; Phone Number: +27665643491; Email: uctmoms@gmail.com
      • Contact: Ernesta Meintjes, PhD; Email: ernesta.meintjes@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age ≥18 yr
• ≤20 wk gestation
• Singleton pregnancy
• Currently heavy drinking (average of ≥15 ml AA/day or binge drinking (≥4 standard drinks/occasion) on at least 1.5 occasions/month on average since becoming pregnant)
• Current choline dietary intake <1 g/day
• Language fluency in English or Afrikaans

Exclusion Criteria:

• Use of methamphetamine or other illicit drugs other than marijuana during the past year
• HIV positive
• Pharmacologic treatment for a serious pre-existing medical condition (e.g., diabetes, hypertension, epilepsy, or cardiac problems)
• Having another child enrolled in the trial from a previous pregnancy
• Plans for mother or child to move away from the area prior to study completion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: High-dose choline supplementation; 2 g choline cation	Dietary supplement: Choline bitartrate; Provided in beverage form
Placebo Comparator: Placebo; Placebo identical to active treatment in appearance, taste, and smell.	Dietary supplement: Placebo; Provided in beverage form

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infant recognition memory	Novelty preference from the Fagan Test of Infant Intelligence	12 months
Postnatal infant weight gain		6.5 months
Postnatal growth in infant head circumference		6.5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infant information processing speed	Processing speed on the Fagan Test of Infant Intelligence	12 months
Postnatal growth in infant length		6.5 months

Collaborators and Investigators

• Sponsor: Wayne State University
• Collaborators: Columbia University; University of Cape Town
• Investigators: Principal Investigator: Sandra W Jacobson, PhD, Wayne State University; Principal Investigator: Joseph L Jacobson, PhD, Wayne State University; Principal Investigator: Ernesta M Meintjes, PhD, University of Cape Town Faculty of Health Sciences; Principal Investigator: R. Colin Carter, MD, MMSc, Columbia University Vagelos College of Physicians and Surgeons

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2023
• Primary Completion (Estimated): October 15, 2027
• Study Completion (Estimated): May 15, 2028

Study Registration Dates

• First Submitted: May 15, 2020
• First Submitted That Met QC Criteria: May 15, 2020
• First Posted (Actual): May 20, 2020

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Growth; Prenatal Alcohol Exposure; Choline Supplementation; Infant Neurodevelopment
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Fetal Diseases; Pregnancy Complications; Alcohol-Induced Disorders; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Fetal Alcohol Spectrum Disorders; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Gastrointestinal Agents; Hypolipidemic Agents; Lipid Regulating Agents; Nootropic Agents; Lipotropic Agents; Choline
• Other Study ID Numbers: R01AA028053 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will make data collected in this study publicly available in accordance with the policies laid out in the NIH/National Institute on Alcohol Abuse and Alcoholism (NIAAA) Data-Sharing Policy for Human Subjects Grants Research Funded by the NIAAA (NOT-AA-18-010; https://grants.nih.gov/grants/guide/notice-files/NOT-AA-18- 010.html). Individual participant data relating to the chief aims of this study data obtained with NIAAA funding will be uploaded to the NIAAA Data Archive (NIAAADA). Only de-identified data will be available to the NIAAADA. A data dictionary will also be available.
• IPD Sharing Time Frame: Per NIAAA policies, data will be made available for sharing with researchers 2 years after the end of the grant or 2 years after the end date of a no-cost-extension, if issued. The end date for data requests will be determined by NIAAA policies.
• IPD Sharing Access Criteria: Per NIAAA guidelines, for research purposes, "investigators at institutions with a Federal Wide Assurance (FWA) will be able to gain access to NIAAADA data by submitting a data access request in accordance with applicable NIAAADA policies (see https://ndar.nih.gov/access.html for sample policies). Data requests will be reviewed and granted by an NIAAA Data Access Committee." The study protocol, statistical analysis plan, and analytic code may be shared by requests to PI Sandra W. Jacobson, PhD.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No