4.2. Strengths and Limitations
Ours is the first observational study in a European country to present objective data on the prescription and dispensing of folic acid in a sample representative of the general population. The power of our study is considerable since we included 186,061 pregnancies recorded over an 11-year period. We exhaustively collected data on the dispensing of folic acid in its dosage form reimbursed by public health insurance, whether for a first prescription or a renewal. Although the EGB represents only 1/97 of the French population covered by public health insurance, this sample is constituted randomly and such that the age and sex distributions are very close to those of the French population [18
], which limits bias in selection of regional patient cohorts. There is, therefore, no reason to suppose that the rate of dispensing in the general population of pregnant women differs from that in our sample.
Moreover, these data are objective and behavioral, unlike those of the largest studies, which used self-report data from questionnaires completed in the postnatal period. These studies also involved much smaller patient samples, such as 14,156 patients in Camier et al., in 2019 [16
] and 12,646 patients in Tort et al in 2013 [15
]. Only the latter study [15
] individualized preconceptional supplementation, whereas the former did not distinguish patients who had preconceptional supplementation from those who received only postconceptional supplementation [16
The main limitation of our study is that we used data on pharmacy dispensing and not data on adherence to treatment. The rate of pharmacy dispensing corresponds neither to the rate of prescription by caregivers nor to the rate of treatment adherence. In effect, a patient can receive a prescription but not fill it at the pharmacy; or, she can fill the prescription but not take the medication. Nonetheless, dispensing data are the best proxy of the intake of prescribed medication. Data on treatment adherence are only available when the taking of medication is directly monitored by a caregiver, which is not feasible in the context of prevention on a population scale.
We may have underestimated the real folic acid supplementation as we did not count the taking of supplements bought over the counter. However, to our knowledge, there is no database that can be used to determine such over-the-counter use by pregnant women. Interestingly, at the population level in France, the total number of unit sales of the two main dosage forms (SPECIAFOLDINE® 0.4 and ACIDE FOLIQUE CCD® 0.4) was estimated between 28% and 36% over-the-counter in 2006, with a decrease down to 8% to 0% in 2016 (source: EGB and data from the global national commercial pharmaceutical industry database GERS®). Consequently, the remaining sales of these two preparations were following a prescription, and therefore being accounted for within the public health insurance national database. Thus, the coverage of the public health insurance national database comprised most folic acid dispensations, up to 92–100% in 2016. Accordingly, we can estimate that the over-the-counter use by pregnant women remains limited.
NTDs arise during the fourth week of pregnancy [2
]. To be effective, folic acid supplementation must be started daily at appropriate doses at least four weeks before conception [12
]. There is a very low rate of preconceptional dispensing in France in the eight weeks preceding pregnancy. One explanation could be that half of pregnancies are unplanned, as shown by Finer and Zolna in the USA [14
]. This could be taken as an argument for mandatory folate fortification, notably of certain foods, as is already the case in some countries [11
]. Furthermore, international recommendations should be clarified if we wish to increase preventive coverage, and the notion of starting supplementation from the beginning of attempts to conceive should be replaced by starting at least one month before conception.
Our findings point to poorer adherence to WHO recommendations [8
] in France than in some other European countries. For instance, in the Netherlands, studies have shown better adherence to recommendations, with self-report data from questionnaires indicating adherence of 37% to 51.6% in the preconceptional period [19
]. However, the prevalence of NTDs in the Netherlands increased from 0.88 to 1.4/1000 pregnancies between 2006 and 2016 [1
]. In Ireland [21
], self-report questionnaires indicate that periconceptional adherence decreased from 45.1% in 2009 to 43.1% in 2013 (n
= 42,042), with a parallel sharp increase in the prevalence of NTDs from 0.59 to 1.31/1000 pregnancies from 2006 to 2016 [1
]. These results raise the question of the validity of the rates of adherence self-reported by patients and/or of the efficacy of prevention by folic acid in these populations. Belgium is the only country to have recorded a large drop in the rate of NTDs since the WHO recommendations, from 1.31 to 0.71/1000 pregnancies between 2006 and 2016 [1
]. In a Belgian study [22
], 41.2% of the women included (n
= 1311) reported having taken preconceptional supplementation and 61% had a first-trimester blood folate concentration above 400 ng/mL, in line with WHO recommendations [23
]. These figures suggest that adherence to WHO recommendations can significantly reduce the prevalence of NTDs in the general population [22
], even in the absence of folic acid fortification of foods, notably flour.
The recommended preventive measures by means of folic acid supplementation in women planning a pregnancy therefore seem generally insufficient or ineffective in most European countries. The prevalence of NTDs in Europe did not decrease between 2006 and 2016, with respective rates of 1.14/1000 and 1.32/1000 pregnancies [1
]. Outside Europe, the failure of supplementation has led 59 countries to mandate folic acid fortification of flour [24
]. This has led to a significant reduction in NTDs in all those countries [9
]. For example, the incidence of NTDs has decreased in the USA and Canada from, respectively, 1.07 to 0.7 and 1.58 to 0.86 NTDs per 1000 live births [25
]. Also in the USA and Canada, the population blood folate concentration rose after fortification [27
The socioeconomic status has been reported as strongly associated with NTDs prevalence, thus questioning the actual contribution of food folate fortification in several countries [28
]. However, mandatory fortification can be considered one of the most effective and cost-effective public health measures to date: the estimated annual economic gain in the USA is 603 million dollars [31
]. In France, the estimated annual cost of adequate folic acid supplementation in the whole population is 14.5 million euros. This cost should be balanced against the cost of caring for the disabled, which over 70 years of life is estimated as 3.3 million euros per person.
Folic acid fortification is currently not in force in any EU countries [11
]. This reluctance is perhaps linked to suspicion of side effects associated with folic acid supplementation or to the costs generated by these public health measures. Nonetheless, a putative association between folic acid and colorectal cancer has been rebutted [32
], and the risks of masked vitamin B12 deficiency do not concern pregnant women at the doses used [32
]. So, in view of these reassuring data, the Scientific Advisory Committee on Nutrition in the UK in 2019 supported the mandatory fortification of flour with folic acid, i.e., the legal requirement to add folic acid to flour, a measure which at the time of writing has not been implemented by the British government [33