Preconception maternal lipoprotein levels in relation to fecundability

Abstract

Study question: Are maternal preconception lipid levels associated with fecundability?

Summary answer: Fecundability was reduced for all abnormal female lipid levels including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total triglyceride levels.

What is known already: Subfecundity affects 7-15% of the population and lipid disorders are hypothesized to play a role since cholesterol acts as a substrate for the synthesis of steroid hormones. Evidence illustrating this relationship at the mechanistic level is mounting but few studies in humans have explored the role of preconception lipids in fecundity.

Study design, size, duration: A secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a block-randomized, double-blind, placebo-controlled trial.

Participants/materials, setting, methods: A total of 1228 women, with 1-2 prior pregnancy losses and without a diagnosis of infertility, attempting pregnancy for up to six menstrual cycles were recruited from clinical sites in Utah, New York, PA and Colorado. Time to pregnancy was the number of menstrual cycles to pregnancy as determined by positive hCG test or ultrasound. Individual preconception lipoproteins were measured at baseline, prior to treatment randomization and dichotomized based on clinically accepted cut-points as total cholesterol ≥200 mg/dl, LDL-C ≥130 mg/dl, HDL-C <50 mg/dl and triglycerides ≥150 mg/dl.

Main results and the role of chance: There were 148 (12.3%) women with elevated total cholesterol, 94 (7.9%) with elevated LDL-C, 280 (23.2%) with elevated triglycerides and 606 (50.7%) with low HDL-C. The fecundability odds ratio (FOR) was reduced for all abnormal lipids before and after confounder adjustment, indicating reduced fecundability. Total cholesterol ≥200 mg/dl was associated with 24% (FOR: 0.76, 95% CI: 0.59, 0.97) and 29% (FOR: 0.71, 95% CI: 0.55, 0.93) reduced fecundability for hCG-detected and ultrasound-confirmed pregnancy, respectively, compared with total cholesterol <200 mg/dl. There was a 19-36% decrease in the probability of conception per cycle for women with abnormal lipoprotein levels, though additional adjustment for central adiposity and BMI attenuated observed associations.

Limitations, reasons for caution: Although the FOR is a measure of couple fecundability, we had only measures of female lipid levels and can therefore not confirm the findings from a previous study indicating the independent role of male lipids in fecundity. The attenuated estimates and decreased precision after adjustment for central adiposity and obesity indicate the complexity of potential causal lipid pathways, suggesting other factors related to obesity besides dyslipidemia likely contribute to reduced fecundability.

Wider implications of the findings: Our results are consistent with one other study relating preconception lipid concentrations to fecundity and expand these findings by adding critically important information about individual lipoproteins. As lipid levels are modifiable they may offer an inexpensive target to improve female fecundability.

Study funding and competing interest(s): This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have declared that no conflicts of interest exist.

Trial registration number: #NCT00467363.

Keywords: cholesterol; fecundity; lipids; lipoprotein; preconception; pregnancy; triglycerides.

Figure 1

Sensitivity analysis comparing the complete-case fecundability odds ratio (FOR) (open circle with dotted line) to the FOR after multiple imputation (MI) of time to pregnancy in 128 women who withdrew using 5000 imputations for each Kaplan–Meier MI (A) and equal-weight MI (B). The triangles on the top right (B only) indicate the FOR's after 100 imputations for a scenario in which all withdrawals with high cholesterol achieved pregnancy. The upside-down triangles (A and B) on the bottom left indicate the FOR's after 100 imputations for a scenario in which all withdrawals with low cholesterol achieved pregnancy. The Xs (A and B) across the bottom indicate the FOR's after 100 imputations for a scenario in which all withdrawals achieved pregnancy and the diamond (A and B) indicates the special case in which all withdrawals achieved pregnancy 1 month after withdrawal. These outside values indicate the area within which the FOR could fall under the assumption of missing not at random. The gray-shaded area indicates a non-significant result (P > 0.05).