Developmental Periods

The pre-embryonic period spans the first two weeks after fertilisation, fertilisation age. It begins at day 0 with fertilisation of the secondary oocyte by a spermatozoon, restoring the diploid chromosome number and forming the zygote.

Over days 1 to 3, the zygote undergoes cleavage, a series of rapid mitotic divisions without any increase in overall size, producing progressively smaller cells called blastomeres. By day 3, a solid ball of 12 to 16 cells, the morula, has formed.

By days 4 to 5, fluid accumulates between the cells of the morula, forming a fluid-filled cavity, the blastocoele, and converting the structure into a blastocyst. The blastocyst has two distinct cell populations: the inner cell mass, which will go on to form the embryo proper, and the trophoblast, the outer cell layer, which will form the placenta and fetal membranes.

Around days 6 to 7, the blastocyst attaches to and begins to implant into the uterine endometrium. Implantation continues over the following days as the trophoblast invades the endometrial stroma.

By day 8, the inner cell mass has organised into a bilaminar embryonic disc, two flat, apposed layers of cells: the epiblast, a columnar layer adjacent to the forming amniotic cavity, and the hypoblast, a cuboidal layer adjacent to the blastocoele. At this stage no organ system exists in any form whatsoever, and the embryo is simply two flat sheets of cells.

The pre-embryonic period follows a distinctive all-or-nothing pattern of vulnerability. The cells of this stage are highly pluripotent and regulative, meaning that if some cells are damaged or lost, the remaining cells can often compensate and restore normal development.

A sufficiently severe insult instead tends to cause death of the conceptus and loss of the pregnancy, frequently before the pregnancy is even clinically recognised, rather than producing a surviving embryo with a structural defect. This period therefore carries very high risk of pregnancy loss but comparatively low risk of surviving structural malformation.

The embryonic period spans weeks three through eight, fertilisation age, and is the period of greatest structural change in the whole of development.

Week 3 is dominated by gastrulation, the conversion of the bilaminar disc into a trilaminar disc through formation of the primitive streak and migration of epiblast cells to establish the three definitive germ layers, ectoderm, mesoderm, and endoderm. Neurulation, formation of the neural tube from surface ectoderm overlying the notochord, also begins during this week.

Weeks 4 through 8 are dominated by folding of the flat trilaminar disc into a three-dimensional, cylindrical embryo, and by organogenesis, the formation of individual organs and organ systems from the three germ layers.

During this window the heart begins to beat, the limb buds appear and differentiate into arms and legs with recognisable digits, and the face forms through fusion of several facial prominences.

Rudimentary versions of essentially every major organ system, cardiovascular, respiratory, gastrointestinal, urogenital, nervous, and musculoskeletal, are established.

By the end of week 8, the embryo has a recognisably human external form, with a distinct head, trunk, and limbs, and every major organ system exists in at least primordial structure, even though none is yet functionally mature. The embryo is approximately 3 centimetres in crown-rump length at this point.

The embryonic period represents the period of maximum sensitivity to teratogenic malformation in the entire course of development.

Each individual organ system has its own specific critical period, a narrow window within weeks 3 to 8 during which a teratogenic insult produces a specific, characteristic structural defect in that organ. It is during this period that the great majority of major structural congenital anomalies originate.

The fetal period spans week 9 until birth, and is characterised predominantly by growth, histological maturation, and functional development of structures that were already established during the embryonic period, rather than by the formation of entirely new structures.

Growth in length and weight is substantial and continuous throughout this period, and accounts for by far the greatest increase in overall size over the course of pregnancy.

The embryo increases in crown-rump length only modestly during the embryonic period, but the fetus increases dramatically in both length and weight during the fetal period, reaching term size and weight by 40 weeks gestational age.

Histological maturation proceeds within organs whose gross structure is already established:

• the lungs undergo progressive branching and, later, alveolar development and surfactant production
• the kidneys continue nephron formation
• the gut undergoes maturation of its muscular and mucosal layers
• the skin develops its full layered structure

Functional maturation is most prominent in the nervous system, which continues extensive structural development, including neuronal migration, synapse formation, and myelination, throughout the fetal period and well beyond birth.

This makes it the organ system with the longest window of developmental vulnerability of any in the body.

The fetal period carries a substantially lower risk of major structural malformation than the embryonic period, since the basic structural plan of every organ is already complete by its start.

It remains a significant period of risk for growth restriction, functional and physiological impairment, and disruption of organs still undergoing active maturation, the central nervous system most importantly.