Cholesterol is an essential morphogenetic cofactor in developmental pathways that pattern the central nervous system during gastrulation and early embryogenesis. Adequate cholesterol is also an essential substrate for the rapid growth of neural tissues in the embryo and for synthesizing pregnancy-related steroid hormones. These critical morphogenetic events begin at embryonic day 14, prior to the establishment of a blood-brain barrier or feto-placental circulation, indicating that the embryo's early requirements may depend on uptake from the maternal circulation. Mothers with abnormally low levels of either total serum cholesterol or any essential lipoprotein fraction during the peri-conceptional period may be unable to supply the developing embryo with adequate cholesterol during this critical phase, resulting in pregnancy loss or the birth of infants with microcephaly and/or neuro-developmental disorders.

Specifically, we predict that mothers whose earliest prenatal total serum cholesterol value is within the lowest 5% of the study cohort will have an excess rate of pregnancy loss and an excess rate of microcephaly and of developmental delay in their offspring. The ALSPAC cohort is ideal for testing this hypothesis, because the number of study participants and the comprehensive pre-and post-natal data obtained from them permit an unbiased, carefully adjusted evaluation of the study hypothesis.