Long-chain polyunsaturated fatty acids, gestation duration, and birth size: a Mendelian randomization study using fatty acid desaturase variants

Abstract

Background: In randomized trials, supplementation of n-3 (ω-3) long-chain polyunsaturated fatty acids (LC-PUFAs) during pregnancy has resulted in increased size at birth, which is attributable to longer gestation.

Objective: We examined this finding by using a Mendelian randomization approach utilizing fatty acid desaturase (FADS) gene variants affecting LC-PUFA metabolism.

Design: As part of a tri-ethnic mother-offspring cohort in Singapore, 35 genetic variants in FADS1, FADS2, and FADS3 were genotyped in 898 mothers and 1103 offspring. Maternal plasma n-3 and n-6 PUFA concentrations at 26-28 wk of gestation were measured. Gestation duration was derived from an ultrasound dating scan in early pregnancy and from birth date. Birth length and weight were measured. Eight FADS variants were selected through a tagging-SNP approach and examined in association with PUFA concentrations, gestation duration among spontaneous labors, and birth size with the use of ethnicity-adjusted linear regressions and survival models that accounted for the competing risks of induced labor and prelabor cesarean delivery.

Results: Maternal FADS1 variant rs174546, tagging for 8 other variants located on FADS1 and FADS2, was strongly related to plasma n-6 but not n-3 LC-PUFA concentrations. Offspring and maternal FADS3 variants were associated with gestation duration among women who had spontaneous labor: each copy of rs174450 minor allele C was associated with a shorter gestation by 2.2 d (95% CI: 0.9, 3.4 d) and 1.9 d (0.7, 3.0 d) for maternal and offspring variants, respectively. In survival models, rs174450 minor allele homozygotes had reduced time to delivery after spontaneous labor compared with major allele homozygotes [HR (95% CI): 1.51 (1.18, 1.95) and 1.51 (1.20, 1.89) for mothers and offspring, respectively].

Conclusions: With the use of a Mendelian randomization approach, we observed associations between FADS variants and gestation duration. This suggests a potential role of LC-PUFAs in gestation duration. This trial was registered at http://www.clinicaltrials.gov as NCT01174875.

Conflict of interest statement

Conflict of Interest Statement: LS, YSC, PCC and KMG have received reimbursement for speaking at conferences sponsored by companies selling nutritional products. They are part of an academic consortium that has received research funding from Abbott Nutrition, Nestle, and Danone. The other authors have no potential conflicts of interest to disclose.

Figures

Figure 1

Directed acyclic graph (DAG) representing the Mendelian randomization approach to estimate the causal effect of LC-PUFA status (E) on gestation duration (O) using FADS genetic variants (G) as instrumental variables. U, V and W denote potential unmeasured confounders, maternal dietary PUFA intake and ethnicity, respectively. Unmeasured factors (U) confound the relationship E→O, but not G→O. Dietary PUFA intake (V) is related to O only through E and therefore cannot confound the E→O or G→O relationships. Ethnicity (W) affects LC-PUFA status (E) through FADS variants (G) and dietary PUFA intake (V) and is therefore a confounder of both the E→O and G→O relationships.

Figure 2

Cumulative incidence of the event of delivery after spontaneous labor according to offspring FADS3 rs174450 variant (major and minor alleles are A and C, respectively). Cumulative incidence function estimates were derived from cause-specific proportional hazards model adjusted for ethnicity (n=1100).