Effectiveness of community-based folate-oriented tertiary interventions on incidence of fetus and birth defects: a protocol for a single-blind cluster randomized controlled trial

Birth defects, known as congenital anomalies or congenital malformations, are structural or functional anomalies that occur during intrauterine and can be identified before and after delivery [1]. Birth defects are a life-threatening cause leading to neonatal death, stillbirth, and long-term disability, which significantly influences individuals’ physical and mental health, health-care systems, families, and societies [2]. An estimated 303,000 newborns die within 4 weeks of birth every year caused by congenital anomalies [3]. Congenital heart defects (CHDs), oral clefts, hydrocephalus, neural tube defects (NTDs) and mental retardation are the most common birth defects in China. Genetic, infections, nutritional or environmental factors involved in the development of congenital anomalies. Among them, the role of folate in organogenesis and birth defects has been widely studied.

The protective effect of folic acid supplementations on several birth defects is well-established [4‐6]. The efficacy of folic acid in preventing the occurrence and the recurrence of NTDs has been conclusively demonstrated through randomized controlled trials (RCTs) and has been confirmed in a public health campaign to ask women preparing for marriage taking a pill containing 400μg of folic acid till the end of their first trimester of pregnancy conducted between 1993 and 1995 in China [4, 5]. Red blood cell (RBC) folate concentrations above 400 ng/mL (906 nmol/L) has been recommended as the optimal cut-off level to achieve the greatest reduction of NTDs for women of reproductive age [7]. Populations based studies also showed strong evidence on folic acid supplementation reducing the occurrence of congenital heart disease (CHD) [8, 9]. And a reduction of CHD subtypes prevalence, such as conotruncal defects and coarctation of the aorta, was found being strongly related to periconceptional food fortification with folic acid [8]. The protective effect of folic acid supplementation reducing other outcomes has also been observed, such as cleft lip and palate, miscarriages or other birth defects [10‐12]. However, the association between folic acid and the cleft lip was largely inconclusive for lacking RCTs evidences [13].

Insufficient folic acid intake and abnormal folate metabolism are the main determinants to folate status. Multiple single nucleotide polymorphisms (SNPs) in folate metabolism pathway genes are common causes of unclear low folate status in women who take sufficient folic acid. The C677T polymorphism on 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene which encodes the pivotal metabolic enzyme can reduce the MTHFR enzyme activity and lower maternal folate status, and increase the susceptibility of NTDs and CHDs [14, 15]. Studies showed SNPs in folate metabolism pathway genes may increase the risk of CHDs via different mechanisms [16‐19]. Therefore, it is necessary to consider folate metabolism ability in performing the individual folic acid supplementary guidance.

The importance of sufficient folate nutrition during the periconception period to fetal development is widely known and many countries have fortified foods with folic acid. However, more than half of women in those countries failed to achieve the optimal folate status at childbearing age [20], which may result from individual genetic variations. We believe that preconception-initiated folic acid supplementation to achieve the recommended folate levels before pregnancy, based on the current RBC folate status and the genetic background of women of reproductive age, will exert a strong effect on primary prevention of both fetus and birth defects. We designed a community-based cluster-randomized controlled intervention trial to evaluate the effectiveness of the procedures on the incidence of fetus and birth defects.

It is a consensus that peri-conceptional folic acid supplementation can prevent fetus and birth defects, and many countries adopted different strategies and procedures to improve population folate nutrition levels during periconception period. However, few studies focused on achieving the optimal RBC folate status before pregnancy. The present study will evaluate the effectiveness of the package of interventions to a high risk group among the entire population based on the current individual folate examinations on the reduction of the incidence of fetus and birth defects. The used intervention procedures that were integrated into the community-based routine peri-conceptional primary care service will be generalizable and helpful for improving practice of primary prevention of the defects.

Our primary outcome may be influenced by several factors. Firstly, since some pregnancy is un-planned, participants in the intervention arm may fail to achieve the optimal folate level before pregnancy and may reduce the intervention effectiveness. Secondly, some participants receiving individual folate guidance may poorly comply with our suggestion of reevaluating folate status to ensure RBC folate concentrations > 906 nmol/L before they plan to get pregnant. This will reduce the intensity and effectiveness of interventions because our critical interventions focused on peri-conception. Considering these situations, we collect participants’ blood samples when they attend the first antenatal care at early pregnancy (within 14 weeks of the last menstrual period) for examination of folate levels. This will help us to obtain a RBC folate levels that are close to the critical window of defects occurrence, since RBC folate is stable and can reflect the folate status of the latest two-three months. Besides, for humanitarian reasons and maternity and child health, we provide interventions during pregnancy and after delivery to both groups, doing this may also reduce the chance of finding group difference in effectiveness of interventions. In the pre-conception recruitment, only participants who get pregnant during the study period will be valid study subjects and included for the outcome analysis. Since the low birth rate in Shanghai, we will expand recruitment to ensure enough sample size for the primary outcome.

The use of individual randomization would be impractical because participants tend to be contaminated and interfere with the interventions. Therefore, a cluster-randomized clinical trial study is performed. The trial is conducted based on community-based health care centers that provide routine primary maternity and child care service. This system will improve the compliance of participants because the general practitioner has close connections with the women from their community.

The intervention has several advantages over routine health care: (i) Pre-pregnancy interventions are an individualized, comprehensive intervention program that references the questionnaire, genes, and nutrient levels in the blood; (ii) This intervention study builds a complete health-care network from pre-pregnancy to childbirth, from community to hospital, which could be widely applied in the future; (iii) This community-based cRCT study could provide a good representation of the study population. The results of this trial will provide evidence on the prevention of fetus and birth defects in primary care settings.

The Protocol Version is 1.0. The trial is prospectively registered at ClinicalTrials.​gov with identifier number NCT03725878 on Oct 31, 2018. Recruitment started on Nov 1, 2018, and the study is currently recruiting participants and collecting pregnancy associated information.