Trial Information

Follow-up Study of Late Effects of Periconceptional Folic Acid in Mothers and Offspring in the Community Intervention Program Population: The Chinese Children and Families Study

Periconceptional folic acid supplements of 400 (Micro) daily prevent neural tube defects
(NTD) in offspring. Some data suggest that periconceptional folic acid supplements, folate
levels during pregnancy, and/or certain variants in the gene that encodes
methylenetetrahydrofolate reductase (MTHFR), a key enzyme that catalyzes synthesis of
5-methyltetrahydrofolate [the primary methyl donor in most metabolic pathways involving
methylation including DNA methylation] from 5,10 methylenetetrahydrofolate may be associated
with reduced risks of certain adverse events during the prenatal period, birth weight and
certain serious diseases in offspring, while other studies have raised concerns about
increased risks of specific serious disorders. Only one study has examined late health
effects in mothers that might be associated with use of periconceptional folic acid
supplements.

We propose to study potential health benefits and adverse effects of periconceptional folic
acid supplements in a 15-year follow-up of offspring and mothers. In the offspring, we will
evaluate whether periconceptional folic acid supplements reduced risk of external congenital
birth defects and childhood acute lymphoblastic leukemia, and whether risks are reduced or
increased for other pediatric disorders linked with periconceptional folic acid supplements
including asthma, pervasive developmental disorders and autism, diabetes, obesity and blood
pressure. In the mothers, we will assess cardiovascular diseases and associated risk
factors, breast and colorectal cancers and precursor conditions, and other cancers. We will
also conduct exploratory assessment of other serious diseases in mothers.

To increase the limited data on the morbidity and survival of children born with a major
birth defect, particularly in low- or middle-income countries, we plan to assess morbidity
and mortality outcomes in children identified with neural tube defects as part of our
follow-up.

The women and children who participated in the joint China-U.S. Community Intervention
Program (CIP) trial (N=243,779 women treated or not treated with folic acid in the
periconceptional period and their offspring) represent unique cohorts whose periconceptional
exposure to folic acid is well documented. We propose to follow a sample of 22,000 CIP
mothers and their offspring (currently 14 to 17 years of age), to ascertain vital status,
medical history, and lifestyle habits. The study will clarify whether there are differences
with respect to growth, physical development during the puberty period, selected serious
morbidity and mortality in offspring and risks of serious health outcomes and mortality in
mothers associated with periconceptional folic acid supplements. Data from this study will
inform us about cohort participation rate, cost, and effective approaches for future
follow-up of the full cohort.

The current protocol focuses on a pilot study (Pilot Study # 1) in which we will carry out
two specific aims in 500 families. We will test and evaluate the most effective approaches
to trace the mothers who enrolled in the CIP in 1993-1995 in CIP counties, fathers, and
children. If the child is not living with the biological mother, we will trace the caretaker
or next of kin with whom the child is living. We will also conduct in-person interviews,
obtain anthropometric and blood pressure measurements and determine cohort participation
rate in a sample of 500 CIP families from two of the 21 CIP project counties to obtain
health information, medical history, and vital status. We will attempt to enroll in the
pilot study 500 mothers/caretakers and 500 offspring, and 500 fathers (Total N=1500).
Excluded from the Pilot Study #1 at this time are the families in which the mother or the
child is deceased. We will seek permission from the IRB to enroll these families at a later
date.