Abnormal Fertilisation and Early Development

Fertilisation and preimplantation development are reliable but not error-free. These errors account for a large proportion of human pregnancy loss. Most occur so early that the pregnancy is never clinically recognised.

Polyspermy is fertilisation of a single oocyte by more than one spermatozoon. It occurs when the normal block to polyspermy fails or acts too slowly relative to the arrival of additional sperm. The block has two components: a fast electrical block and a slower, cortical granule-mediated zona reaction.

A polyspermic zygote receives more than one paternal haploid genome in addition to the single maternal haploid genome. The chromosome complement is grossly excessive, most commonly triploid: three complete haploid sets rather than the normal two.

Triploid conceptions are almost always incompatible with ongoing development and cause very early pregnancy loss. They are a recognised, distinct cause of miscarriage. Some are associated with a specific abnormal pattern of placental overgrowth, depending on the parental origin of the extra chromosome set.

A zygote can carry an abnormal chromosome complement for reasons other than polyspermy. The most important is nondisjunction or anaphase lag during meiosis in either parent's gametogenesis. This produces a gamete with an incorrect chromosome number, which is incorporated into the zygote at fertilisation and results in trisomy or monosomy for the affected chromosome.

An abnormal complement can also arise after fertilisation, during one of the zygote's own early postzygotic mitotic divisions. This produces a mosaic conceptus in which different cells carry different chromosome complements.

This mechanism differs from a gametogenesis error and carries different implications for prognosis and recurrence risk. A postzygotic mosaic error does not in itself predict the parents' own future reproductive risk, whereas a gametogenesis-derived error can.

Failed or arrested cleavage describes a conceptus that does not progress normally through the expected cleavage divisions. It either arrests entirely at an early cell stage without further division, or divides at a markedly abnormal or irregular rate or pattern.

Causes include:

• A chromosomally abnormal zygote, in which the abnormal genetic complement disrupts the cell cycle machinery required for continued division.
• A defect in maternally supplied cytoplasmic factors. The earliest cleavage divisions depend largely on maternal RNA and protein stores accumulated in the oocyte during oogenesis, rather than on the zygote's own gene expression, which does not become fully active until slightly later.
• Other, less well-characterised disruptions of the cell division machinery itself.

A conceptus that arrests during cleavage does not reach the morula or blastocyst stage and cannot proceed to implantation.

A conceptus can progress through cleavage but then show abnormal compaction, abnormal blastocyst formation, or an abnormal ratio or distribution of cells between the trophoblast and inner cell mass populations.

Any of these can compromise the conceptus's capacity to implant successfully. They can also impair normal further development, even if implantation does occur.

The great majority of these abnormalities share a common outcome. They include polyspermy, an abnormal chromosome complement arising from gametogenesis or from a postzygotic error, failed cleavage, and abnormal blastocyst formation. The conceptus fails to implant successfully or, if implantation occurs, the pregnancy fails to continue beyond a very early stage.

This is the embryological basis for the observation that a very large proportion of human conceptions are lost so early that the loss is never clinically recognised as a pregnancy. It is frequently perceived, if at all, only as a delayed or slightly heavier than usual menstrual period.

Chromosomal and structural abnormality arising during fertilisation or the preimplantation period is understood to be the leading identifiable cause of loss at this stage. It is more common than the causes of clinically recognised miscarriage occurring later, after a pregnancy has been confirmed.