The metabolic syndrome (MetSyn) is characterized by a cluster of metabolic risk factors including abdominal obesity, DM or insulin resistance, non-white ethnicity [4], dyslipidemia, chronic hypertension and elevated inflammatory highly sensitive serum C-reactive protein (hsCRP) [5]. Since 40% of Western teenagers exhibit a sedentary lifestyle [6] and 5–16% are obese [6,7], MetSyn is now seen in 15% of women who are in their reproductive years [8].

For each case, five maternal controls without an NTD-affected pregnancy were randomly selected within a +/- 24-month period. Serum samples, originally collected at the time of MSS in the index singleton pregnancy, were frozen at -70°C. Each frozen sample was thawed and analyzed for hsCRP using the DPC Immulite 2000 immunoassay analyzer (Diagnostic Products Corporation, Los Angeles, CA), whose functional sensitivity is 0.2 mg/L, with within- and between-run CVs of 2.8 % and 3.1 % at 3.2 mg/L, and 3.4 % and 3.8 % at 21.8 mg/L, respectively. Serum folate was analyzed using the Bayer Centaur immunoassay analyzer method (Bayer Diagnostics Division, Toronto, ON). The distribution of serum hsCRP and folate values was positively skewed, so we log-transformed these measures and used inverse transformations to generate geometric means and standard deviations (SD).

Mean serum hsCRP were 6.1 and 6.4 mg/L in the cases and controls, respectively (Table ​(Table1).1). When hsCRP was excluded from the model, the crude OR for NTD were 1.9 (1.2–3.1) and 6.1 (1.2–30.9) in the presence 1 and 2 or more features of MetSyn, respectively, relative to none (trend p = 0.001) (Table ​(Table2).2). The corresponding adjusted OR were essentially the same (Table ​(Table2).2). With hsCRP included as a feature of MetSyn, the adjusted OR for NTD was 1.6 (0.88–2.8) in the presence of 1 feature, and 3.1 (1.2–8.3) in the presence of at least 2 features, relative to none (trend p = 0.009) (Table ​(Table22).

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 [12,13]. Furthermore, maternal weight and body mass index (BMI) are highly correlated [14,15], 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 [8,17,18]. 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 [2,3]. 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.