Strengths and limitations
This study is based on self-reported measures of folic acid consumption and does not contain information regarding formulation, dosage, or timing of initiation of folic acid. As the data were collected after delivery, it is possible that report bias has occurred; however, this bias will be, from the best of the authors’ knowledge, non-directional and will, therefore, not change the direction of the findings. The bias might affect the power of the study: this has been taken into account with a coherent sampling strategy, resulting in a large sample size. Maternal dietary factors and consumption of vitamins may also impact on the effect of folate on cleft lip and palate and women not taking folic acid supplements may be less likely to have healthier habits during pregnancy; these factors were not covered in the initial questionnaire in detail.
In addition, the caseness of cleft lip and palate was based on parental self-report. Based on the study governance of Growing Up in Ireland, it was not possible to validate against medical records. It is not likely that recall or report bias would change the direction of the association; however, as a potential link between folate and cleft lip and palate is not discussed in the media, public knowledge of it seems unlikely.
Difficulties in detecting population changes in rare conditions such as congenital anomalies limit studies trying to detect protective behaviours. Furthermore, it is not possible to rule out the effect of unknown confounders. The study design does allow an assessment of a statistical association between folate intake and cleft lip and palate, but no formal assessment of causality can be done. However, a major strength of this study is the large and representative nature of the sample, which equated to approximately one-seventh of all births in Ireland in 2007.15 This study’s results take cleft lip and palate and cleft palate into account.
Comparison with existing literature
A study from England found that, although 88.9% of women reported taking folic acid supplements before their 18-week antenatal clinic appointment, 51.6% of those surveyed did not take folic acid supplement before 4 weeks’ gestation.17 Internationally, in a systematic review of 52 studies, in some 20 (mainly Western) countries between 1992 and 2001, the reported periconceptional supplement use ranged from 0.5% to 52%.18
Similar to previous studies, these findings showed that not taking folic acid was more common in women of low socioeconomic status. An earlier Irish study using data collected from 300 women attending a maternity hospital found professional class and planned pregnancy to be the main predictors of periconceptional use of folic acid.10 A recent study from New Zealand found that younger maternal age, increasing parity, minority ethnic group, lower education, and lower income predicted poor folic acid intake in expectant mothers.19
The cleft lip and palate prevalence of approximately 1.98 per 1000 births was similar to that of a recent Dutch study, which reported a prevalence of 1.68 per 1000 births.20 Although there is no national registry of cleft lip and palate in Ireland, four regional Irish cleft lip and palate registers reported prevalence estimates between 1.17 and 2.02 per 1000 births in 2008–2009.21 The current study is thought to be the first formal estimate of the prevalence of cleft lip and palate in a nationally representative Irish cohort.
Previous research from the International Database of Craniofacial Anomalies suggests that Ireland has a high rate of cleft lip and palate compared with the European average, which is reported as 1.4 per 1000 births (no CI available).22 Similarly, the prevalence of cleft lip and palate in the UK ranges from 1.32 to 1.78 per 1000 births.17 It is of interest that the prevalence of cleft lip and palate was higher in northern Europe (1.73 per 1000 births) compared with its prevalence in southern Europe (0.87 per 1000 births), although no explanation for this has been suggested.22 Although promotion and awareness of the benefits of folic acid have been ongoing in Ireland over the last two decades, a concomitant reduction in the prevalence of neural tube defects has not been found.23
The potential protective effect of folic acid on cleft lip and palate, as illustrated in Figure 1, is consistent with findings from a number of case–control studies, although significance levels vary considerably. A small Hungarian cohort control study found an insignificant OR of 1.00 (95% CI = 0.20 to 4.95),24 whereas another case–control study found an OR of 0.60 (95% CI = 0.39 to 0.92) with regard to the effect of folic acid supplementation on the rate of cleft lip and palate.25 The corresponding crude OR of 0.23 in this study is in line with the findings from the latter study, and comparable considering the CIs used (95% CI = 0.08 to 0.65).
In contrast to this study, a recent Cochrane review of the effect of folic acid on cleft lip or cleft palate found insufficient evidence to support the protective effect of folic acid. This was largely owing to insufficient cases of the defect occurring in the trials.5 The plausibility of folic acid in preventing cleft lip is indirectly supported by the higher prevalence of cleft lip and palate among pregnant women taking drugs that can act as folic acid antagonists, such as phenytoin and phenobarbitone.7
Previous research addressed confounding in several ways. Several studies included an adjusted OR, controlling for a wide range of variables including smoking, alcohol consumption, maternal age, education, employment during early pregnancy, sex of infant, year of infant’s birth, family history of cleft lip and palate, maternal epilepsy and diabetes, and whether pregnancy was planned.13,14 The adjusted OR in the present study did not differ significantly from the crude OR.
