Introduction

Maternal folic acid supplementation (FAS), when taken prior to and during pregnancy, is protective against the development of neural tube defects (NTDs) such as spina bifida and anencephaly, [1, 2] low birth weight, and megaloblastic anemia in mothers [3–6]. Annually, 260,100 NTD-affected pregnancies occur worldwide, constituting a significant part of the neonatal burden of care [3–6]. Fortification of staple foods with folic acid is common in numerous countries but where this has not been done, as in the United Kingdom (UK), FAS remains essential.

Ankyloglossia, or tongue-tie, is a condition that occurs when the tongue is tethered to the floor of the mouth by a short, thickened strip of tissue called the lingual frenulum [7, 8].This can make it difficult to move the tongue and may interfere with breast feeding. In some cases, ankyloglossia may also cause difficulty with speech [8]. Ankyloglossia can be treated with a minor surgical procedure, frenotomy, to release the lingual frenulum. The procedure is considered low-risk, in part as no general anesthetic is used [7, 9–12]. Ankyloglossia can also be treated non-surgically through speech therapy and lactation support [7].

The prevalence of ankyloglossia ranges from 2.8% - 10.7% globally [13, 14]; this variation is likely due, in part, to a lack of consensus on the diagnostic criteria. In recent years, there has been an increase in reported cases of ankyloglossia, primarily in high-income countries (HICs), thought to be due to an increased focus on breast feeding, a growing awareness of the condition, and the availability of treatment options [9]. However, in the non-academic literature, concerns have been raised among women of reproductive age and some health professionals in the UK and USA, of a causal relationship between FAS, particularly after the first trimester, and ankyloglossia (Mothering.com, Netmums.com). Currently, the clinical consensus is that FAS for preventing NTDs must begin at preconception [15]. Media reports suggesting a causal relationship between folic acid supplementation and ankyloglossia could affect FAS adherence, increasing NTDs.

This study aimed to conduct a systematic review of the scientific literature to identify and summarise evidence on the relationships between maternal FAS during preconception and pregnancy and the risk of ankyloglossia in the offspring.

Materials and methods

Results

Article selection

As shown in Fig 1 [17], the database searches yielded 73 articles after duplicates were removed. Titles and abstracts were critically reviewed by GR and JH against the inclusion criteria, and articles that were not relevant were excluded, leaving 26 articles for which full-text papers were retrieved and reviewed. One article remained for inclusion in analyses, as shown in Table 1. The reference lists of these articles were reviewed, but no additional studies were found.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Fig 1. Flow diagram: Article selection process.

https://doi.org/10.1371/journal.pone.0294042.g001

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Final article selection.

https://doi.org/10.1371/journal.pone.0294042.t001

There was only one study, conducted in Israel and published in 2020, directly assessing the relationship between FAS and ankyloglossia [18]. This case-control study reported that regular intake of FAS preconception was higher in women with infants diagnosed with ankyloglossia. Further details of the study are shown in Table 1. There were no studies looking at FAS after the first trimester.

Discussion

This systematic review of the literature shows that there is currently no clear evidence to support a relationship between folic acid supplementation after the first trimester and ankyloglossia. This is an important finding as it shows that there are no empirical grounds for the circulating media reports, to the contrary, such reports could adversely affect adherence to folic acid supplementation leading to an increase in NTDs. The only available evidence on a relationship between FAS and ankyloglossia was from a case-control study examining preconception folic acid intake, judged to have a high risk of bias through an inadequate selection process, incomplete reporting, and lack of clarity over the measurement of FAS intake and the definition of the ‘periconception’ period. Even if it had been well-conducted, as a case-control study it would rank lowly in the hierarchy of evidence, particularly given the lack of other supporting evidence.

There is, currently, no research evidence supporting a mechanism by which FAS might increase the risk of ankyloglossia in infants. Amitai et al. proposed that excessive folic acid during organogenesis (with no specific time frame specified) might result in tighter closure of mid-line structures, resulting in excess connective tissue at the base of the tongue, including the lingual frenulum [18]. One other potential mechanism has been proposed, relating to unmetabolized folates following folic acid supplementation [19]. However, in a randomized controlled trial testing the levels of plasma unmetabolized folates between women taking low and high doses of folic acid, no significant difference in unmetabolized folates was observed between the group [20].

Further research is needed to investigate the association between FAS (both before and during pregnancy) and ankyloglossia. Were any relationship found, subsequent research should explore the potential mechanisms by which folic acid supplementation could increase the risk of ankyloglossia in infants. If a link were identified this would then enable clinicians and women to make an informed decision around FAS, balancing the risk of the potentially life-threatening outcome of NTD and other known benefits of FAS on birthweight, child development, and cognition [21–23], with the risk of ankyloglossia in the infant if FAS is continued throughout pregnancy.

The timing of folic acid supplementation is essential for efficacy. Neural tube closure should occur by the fourth week of pregnancy; if the neural tube fails to close by then, malformations in the brain and spine, such as anencephaly and spina bifida, can occur [15]. Unfortunately, many people do not know they are pregnant until that window of opportunity has closed [2]. Therefore, to prevent NTDs, folic acid should be taken starting from at least one month before conception until the end of the first trimester to ensure that maternal folate levels are sufficient in the early stages of pregnancy when neural tube closure occurs [24, 25]. It is difficult to get enough folate from diet alone [26]; around 80 countries, including the USA, Canada, Chile, and South Africa, have mandated the fortification of staple food products, such as corn and wheat, with folic acid to increase folate levels in the population and decrease adverse health outcomes [27, 28]. In 1998, in the USA, the FDA required that all enriched grain products be fortified with folic acid [29]. Since then, an estimated 1,300 NTDs have been prevented annually (about a 30% reduction in prevalence), saving an annual total of US$508 million [29]. Furthermore, studies analyzing the rates of congenital malformations after mandated wheat fortification suggest that it may be protective against congenital disabilities other than NTDs [3, 30–32]. In September 2021 the UK government decided to proceed with mandatory fortification of non-wholemeal wheat flour with folic acid. However, this decision has been met with criticism regarding the agreed-upon dosage, which is considered inadequate [27], and the policy has yet to be implemented.

In light of these large-scale results spanning several decades and countries, the evidence presented in the Amitai study does not suffice to change clinical practice and recommendations, and extensive, experimental, and clinical research is needed to establish a compelling causal link.

Conclusion

There is no strong evidence of a causal relationship between folic acid supplementation and ankyloglossia. At the current time, the known benefits of folic acid supplementation in the preconception period and during pregnancy far outweigh the potential risks, with overwhelming evidence to support supplementation before and during pregnancy. These benefits must be clearly communicated to patients by their clinicians during preconception and antenatal care.

Supporting information