Maternal periconceptional seafood intake, pregnancy complications, and fetal growth

Abstract

<bold>Background</bold>: Seafood intake has well-known health benefits that include cardiometabolic benefits. However, associations of maternal seafood intake, particularly intake of different seafood subtypes, with course and outcomes of pregnancy have not been fully described. Findings have been inconsistent and the role of seafood-related healthy nutrients (e.g. n-3 long chain polyunsaturated fatty acids, eicosapentaenoic acid [EPA; 20:5n-3] and docosahexaenoic acid [DHA; 22:6n-3]) and adverse contaminants (e.g. mercury and cadmium, Cd) in these associations is largely unknown. Further, a significant gap remains in understanding of potential mechanisms underlying associations of maternal seafood intake with pregnancy complications and/or fetal growth. <bold>Objectives</bold>: The specific aims of this dissertation project were to (1) investigate associations of maternal periconceptional seafood intake with pregnancy complications, (2) investigate associations of maternal periconceptional seafood intake with fetal growth, and (3) investigate associations of maternal Cd burden with sex-specific placental genome-wide DNA methylation. <bold>Methods</bold>: Investigations to address specific aims #1 and #2 were conducted among pregnant women enrolled in the Omega study, a prospective cohort study of risk factors for pregnancy complications among Pacific Northwest residents (1996-2008). A food frequency questionnaire administered at 16 weeks gestation, on average, was used to assess intake of shell-, lean-, and fatty-fish, EPA and DHA. Seafood intake was categorized into frequencies of: <0.5 ounces/month (oz/mo), 0.5 oz/mo-<1.5 oz/week (oz/wk), 1.5-3 oz/wk, and >3 oz/wk. Blood samples were analyzed for erythrocyte membrane fatty acids, including EPA and DHA, among a randomly selected subset (60%) of initial Omega study participants (enrolled from 1996-2000, N = 586). Using medical records, we ascertained diagnoses of preeclampsia (PE), pregnancy induced hypertension (PIH), gestational diabetes (GDM), and preterm birth (PTB) as well as fetal growth indices: birth weight (continuous, low birth weight [<2,500 g], or macrosomia [≥4,000 g]), birth length, ponderal index, and head circumference. We fit generalized linear models with a log link, Poisson family, and robust standard errors to estimate relative risks (RRs) and 95% confidence intervals (CIs) for pregnancy complications (PE, PIH, GDM, and PTB) and abnormal fetal growth indicators (low birth weight or macrosomia) across seafood intake categories. We used linear regression models to estimate mean differences and 95% CIs for continuous fetal growth indices across seafood intake categories. Investigations to address specific aim #3 were conducted among women who delivered at Swedish Medical Center and provided placental samples (N = 24). Placental Cd was quantified by inductively coupled plasma mass spectrometry. Placental genome-wide DNA methylation was profiled using the Infinium HumanMethylation 450 BeadChip. We used infant sex stratified ANOVA models to examine associations of Cd high/low status with methylation (at each CpG site or genomic region). <bold>Results</bold>: Median (interquartile range) of shell-, lean-, and fatty-fish intake was 0.8 (0-2.8), 1.4 (0-2.9), and 1.5 (0.4-3.0) oz/wk, respectively. Lean fish intake of >3 oz/wk (versus <0.5 oz/mo) was associated with a higher risk of PTB (RR= 1.55, 95% CI: 1.04-2.30). In addition, lean fish intake of >3 oz/wk (versus <0.5 oz/mo) was associated with a 2.2-fold higher risk of low birth weight (RR= 2.23, 95% CI: 1.21-4.09). Shellfish intake of >3 oz/wk (versus <0.5 oz/mo) was associated with a higher mean ponderal index (0.64 kg/m3 higher, 95% CI: 0.04-1.25 kg/m3). There was no evidence for associations of shell-, lean-, or fatty-fish intake with other pregnancy complications or other fetal growth indices. Intake of total seafood (all subtypes combined), dietary EPA+DHA, or maternal erythrocyte EPA+DHA was not associated with pregnancy complications or fetal growth indices. Medians of placental Cd among female and male infants were 5 ng/g and 2 ng/g, respectively. Among female infants, high placental Cd (≥5 ng/g) was associated with hypomethylation of three CpG sites (near ARL9, SIAH3, and HS3ST4) and one genomic region on chromosome 7 (included genes CROT and TP53TG1) (FDR adjusted p-value <0.10). Among male infants, high placental Cd (≥2 ng/g) was associated with differential methylation of three CpG sites, two (hypomethylated) near MECOM and one (hypermethylated) near SALL1, and two genomic regions (hypomethylated), one on chromosome 3 (included MECOM gene) and one on chromosome 8 (included ARHGEF10 gene) (FDR adjusted p-value <0.10). <bold>Conclusion</bold>: Our results suggest that associations of seafood intake with pregnancy complications, and fetal growth may vary by seafood subtype. Specifically, higher lean-fish intake was associated with higher risk of PTB and higher risk of low birth weight. Further, higher shellfish intake was associated with a higher mean ponderal index. Our pilot study provides suggestive evidence for sex-specific associations of placental Cd with differential placental DNA methylation. Replication efforts and mechanistic investigations are potential future areas of research. Such investigations can inform preventative activities to improve course and outcomes of pregnancy.