Association of maternal risk factors with the recent rise of neural tube defects in Canada

Abstract

Background We sought to assess the recent trend in NTD prevalence at birth in the post‐folic acid food fortification era and to identify the maternal risk factors associated with that trend. Methods We carried out a population‐based study of all livebirths and stillbirths (including late pregnancy terminations) delivered in hospitals in Canada (excluding Quebec) from 2004 to 2015 (n = 3 439 330). We examined NTD birth prevalence by year, multiple pregnancy, maternal age, parity, pregestational diabetes, chronic illness, and problematic substance use. Poisson regression was used to quantify the association between spina bifida and cranial defects and maternal characteristics and other risk factors. Results We identified 1517 non‐chromosomal NTDs, yielding a birth prevalence of 4.4 per 10 000 total births. NTD prevalence rose from 3.6 in 2004 to 4.6 per 10 000 in 2015 (Ptrend = 0.03). Among NTD subtypes, only spina bifida showed a temporal increase (Ptrend = 0.03). Birth prevalence of spina bifida was higher among younger mothers, those with type 2 diabetes (rate ratio (RR) 3.74, 95% confidence interval (CI) 2.21, 6.35), chronic illness (RR 3.16, 95% CI 1.97, 5.07), and problematic substance use (RR 1.88, 95% CI 1.31, 2.71). Adjusting for risk factors attenuated the significant temporal trend in spina bifida (unadjusted average annual prevalence ratio (aAAPR) 1.016, 95% CI 1.001, 1.032; adjusted AAPR 1.014, 95% CI 0.998, 1.029). Conclusions Increases in the frequency of maternal risk factors such as pregestational diabetes mellitus, substance use, and chronic illness may be partly responsible for the recent rise in NTDs, particularly spina bifida.

Small head circumference at birth: an 8-year retrospective cohort study in China

“…The association of in utero exposure to teratogens with absolute microcephaly was, however, consistent with previous studies 13 18 19 26 37 38. Exposures to teratogens or substances such as cocaine, opioids and alcohol are known risk factors for microcephaly4 26 37 38 and other neurological developmental abnormalities 27. Another recent study from Quebec, Canada, found that neonatal abstinence syndrome (a proxy for exposure to maternal opioids exposure) was associated with a 16-fold higher risk (adjusted risk ratio 16.4, 95% CI 9.4 to 28.6) of congenital microcephaly 26…”

“…We characterised maternal demographics and risk factors for the three types of microcephaly. We considered maternal age at conception (<25, 25–29, 30–34 and ≥35 years), mother’s ethnicity (Cantonese women vs women migrated from other provinces of China), parity (first vs ≥second child), conception method (IVF vs natural), pregnancy condition (ie, pre-existing hypertension, gestational hypertension, pre-eclampsia/eclampsia, gestational and pregestational diabetes mellitus),17 18 exposure to teratogens (ie, maternal use of substances or behavioural risk factors) including prenatal and/or perinatal use of alcohol, cigarette or medicinal or other illicit or therapeutic drugs13 26 27 and TORCH infections during pregnancy. In addition, we included congenital heart defects and other anomalies as the former has been strongly associated with microcephaly 3 5 13.…”

Periconceptional folic acid and risk for neural tube defects among higher risk pregnancies

“…A recently study commented on the increase in NTD‐affected pregnancies in Canada over the past decade and how these additional cases may be due to increased prevalence of several risk factors including pregestational diabetes and certain conditions which are sometimes treated with AEDs such as epilepsy and mood disorders (Liu et al, ). In addition, despite the high prevalence of obesity and its established association with NTD risk, research is lacking on an appropriate FA dose that might help to reduce, though perhaps not eliminate, NTD risk for this group.…”

The interaction of maternal diabetes with mutations that affect folate metabolism and how they affect the development of neural tube defects in mice

“…FA supplementation reduces the NTDs and other embryopathies described in the offspring of diabetic rodent dams . However, despite the efforts to prevent NTDs through FA supplementation in humans, no such decrease has been detected, and there is even a suggestion that their incidence may increase in association with pregestational diabetes . Significantly, this latter study was performed on a Canadian population where around 38% of the newborns carried the 677C>T allele for MTHFR , associated with reduced enzymatic activity …”

“…[32][33][34] However, despite the efforts to prevent NTDs through FA supplementation in humans, no such decrease has been detected, 35,36 and there is even a suggestion that their incidence may increase in association with pregestational diabetes. 37 Significantly, this latter study was performed on a Canadian population where around 38% of the newborns carried the 677C>T allele for MTHFR, 38 associated with reduced enzymatic activity. 25,31,39 Based on this situation, we set out to explore the possible additive teratogenic effect of these two risk factors on the developing embryo: a diabetic intrauterine environment and the presence of compromised maternal-fetal folate metabolism.…”