Exploring the association of parity and its interaction with history of preterm delivery on gestational duration.

PURPOSE: Preterm delivery is a major cause of child mortality. While the relationship between parity and preterm delivery is known, its association with gestational duration and variability remains underexplored. Differences in variance may suggest interaction with other well-established risk factors. METHODS: With 1.1 million spontaneous deliveries (1990-2012) from the Swedish Medical Birth Register, we assessed while accounting for potential confounders the effects of parity on the mean and variance of gestational duration, and its possible interactions with history of preterm delivery. Pedigrees allowed to account for nonobserved, shared confounders using linear mixed models. RESULTS: Parity has a modest association with mean gestational duration, but a large effect on its variance. For example, the first pregnancy had the shortest mean gestational duration, 0.29 days shorter (95% CI: -0.33, -0.25) than the second, and the largest variance (σ2 = 135 days2). Accounting for shared unobserved confounders highlighted a group effect bias, likely linked to the mothers' total number of offspring. Parity interacts with other risk factors, including previous preterm delivery where the magnitude of its effect increases with parity (up to 4.6 days effect difference). CONCLUSIONS: Nonshared factors across a mother's pregnancies highlight parity's importance to gain insight into the mechanisms governing the timing of delivery.

Time-varying effects are common in genetic control of gestational duration.

Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent-gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31 000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy 'clock'. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new fetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm, periods and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant and should help design further experimental studies.

Time-varying effects are common in genetic control of gestational duration.

Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent - gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31,000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy "clock". We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new foetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm periods, and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant, and should help design further experimental studies.