In the presence of at least one feature of MetSyn in pregnancy, the risk of NTD was nearly doubled. In the presence of two or more features, it was six times higher. Inclusion of hsCRP as a MetSyn feature attenuated these risk estimates considerably.
Our study was limited by the manner in which the features of MetSyn were determined. Its retrospective design enabled us to assess only a sub-set of these features, and neither chronic hypertension nor dyslipidemia [5
] were included herein. While we evaluated self-reported maternal weight, this was not paired with height, nor was it measured before pregnancy. However, there appears to be little variation between self-reported and measured weight in pregnancy [12
]. Furthermore, maternal weight and body mass index (BMI) are highly correlated [14
], as are second trimester and pre-pregnancy BMI [16
]. Our inclusion of women with pre-pregnancy DM did not distinguish between those with type 1 and type 2 DM, nor did our use of broad ethnic categories enable us to account for the additional within-group diversity, including country of birth. Nonetheless, others have emphasized the utility of "non-white" ethnicity as a determinant of risk for MetSyn [8
]. We previously observed that women of First Nations ancestry had about a five times higher risk of NTD compared to White women, which was not so among women of other non-White ethnic origins [19
]. Finally, it was not known how many cases or controls were taking folic acid tablet supplements periconceptionally, a major determinant of NTD risk [1
], although we did adjust for serum folate status at the time of screening, as well as socioeconomic status, which itself is a predictor of periconceptional folic acid supplement use [20
Including hsCRP as a feature of MetSyn attenuated the risk of NTD in this study. A likely explanation is the physiological effect of pregnancy on hsCRP [11
]. This was reflected by an exceptionally high mean hsCRP concentrations among cases and controls [21
], which likely diminished our ability to detect any association, if truly present. Recent evidence from the Framingham Offspring Study suggests that combining hsCRP in a model of MetSyn does not improve the ability to predict cardiovascular disease risk [21
]. Clearly, measuring hsCRP prior to conception, or months after completion of pregnancy, would better a better test of its utility for predicting NTD risk.
Which features of MetSyn best predict the risk of NTD? Shaw and colleagues found that both a high-caloric diet [22
] and a sedentary lifestyle [23
] were independent risk factors for NTD. In their Californian population-based case-control study, the risk of NTD was highest among women who mean dietary glycemic index was in the upper vs. lower quartile (adjusted OR 1.9, 95% CI 1.3–2.7), especially when periconceptional BMI was also elevated (adjusted OR 4.0, 95% CI 1.0–15.7) [22
]. Other studies, including ours, have confirmed the likely role of maternal obesity and DM as risk factors for NTD [2
]. While it may be worthwhile to include both hypertriglyceridemia and chronic hypertension in a MetSyn model of NTD risk, they too are better measured in the non-pregnant state, as they are altered by pregnancy [24
]. Chronic hypertension could conceivably alter the risk of NTD based on the link to maternal hyperhomocysteinemia [25
], but it is possible that there are other biologically plausible explanations.
Fewer than 10% of maternal cases studied herein exhibited two or more features of MetSyn. Nonetheless, because MetSyn is now so prevalent among adults and children [7
], this figure likely has importance at both the individual and societal levels. Most features of MetSyn can be inexpensively determined within an outpatient clinical setting, including measurement of BMI or pre-pregnancy waist circumference, blood pressure and capillary blood glucose concentration. We suggest that women considering pregnancy who are at risk for MetSyn be advised to increase dietary and supplemental intakes of folic acid, and consider a path of healthy eating and regular physical activity. More evidence is needed to determine whether maternal "metabolic modification" [26
] can safely and efficaciously lower the risk of NTD.