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The Placenta
Implantation
After fertilisation, the zygote spends about 46 days travelling to the uterus. It is moved
through the uterine tube by the peristaltic action of the smooth muscle and the sweeping
movements of the cilia and the fluid produced by the ciliated epithelium. The embryo at first
divides approximately every 15 hours; the division time becomes progressively shorter.
During the initial cleavage steps, the embryo is enclosed within the restraining zona
pellucida and its total mass remains approximately constant. Cytoplasmic factors regulate
cleavage, which occurs without net growth so cell number increases but the cells become
progressively smaller. Initially, the cleavage divisions are synchronous and each cell
(blastomere) is identical, but then the cells divide at an independent rate. Later synchrony is
lost, so the pattern of doubling of cell number is also lost.
After the eight-cell stage, the cells change morphologically so some of the cells at the outer
edge of the embryo become flatter. About day 4, as it reaches the uterus, the embryo is a
mass of cells known as the morula (derived from the Latin word for mulberry). A fluid-filled
cavity forms between the inner and outer cell layers; the embryo is now known as a
blastocyst. By the 64-cell stage, the cells of the conceptus are irreversibly differentiated on
the pathway to becoming embryonic or extraembryonic tissue. Differentiation into a particular
cell type is related to positional information of the cells, which induces particular genes to be
expressed. Cells of the blastocyst initially differentiate into two distinct cell lines: the
trophoblast (which will develop into the placenta) and the inner cell mass (which will develop
into the embryo).
The blastocyst may remain free-floating in the uterine cavity until implantation at day 7. The
blastocyst accumulates fluid and expands; and the zona pellucida is shed so the blastocyst
comes into contact with the endometrium (lining of the uterus). Impanation (nidation) of the
blastocyst normally occurs in the upper part of the body of the uterus (the fundal region). The
blastocyst implants at the embryonic pole, where the inner cell mass lies. The outer cells of
the blastocyst secrete proteolytic enzymes and collagenase, which break down and destroy
some of the cells of the endometrium; implantation in humans is a very invasive mechanism.
Uterine muscle activity is low at this time because secretion of progesterone is high.
The extravillous cytotrophoblast cells migrate from the villi beyond the leading edge of
syncytiotrophoblast into the stroma. From about 12 days postfertilization, these cells invade
the maternal capillaries and spiral arteries of the decidua. The extravillous cytotrophoblast
cells initially plug the lumen of the maternal vessels that have been invaded and
subsequently replace the maternal endothelium of these vessels. Plugging of the lumen of
the invaded maternal blood vessels prevents bleeding and is achieved by day 14, which
coincides with the expected date of the next menstrual period. The plugs prevent flow of
maternal blood into the intervillous space in early pregnancy but allow a slow seepage of
plasma. The developing placenta forms an effective barrier between the mother and
developing embryo that persists up to 10 weeks gestation when the trophoblastic plugs are
dislodged and intervillous blood flow is established. It is at this time that peak hCG secretion
occurs. The increasing oxygen level and concomitant oxidative stress also stimulates
cytotrophoblast proliferation and differentiation and the increased expression of antioxidant
enzymes. Embryogenesis occurs in a relatively hypoxic environment. The developing
embryo is thought to be particularly vulnerable to damaging oxygen free radicals during the
sensitive period of organogenesis and the first-trimester placenta has limited antioxidant
capacity; thus, limiting fetal exposure to oxygen may be protective.
Spiral artery conversion
Between the 4th and 16th week of gestation, villus growth and considerable remodelling of the
placenta occur, including remarkable changes to the maternal blood vessels underlying the fetal
placenta ensuring that the spiral arteries are capable of delivering large volumes of blood to the
placental intervillous spaces at an appropriate rate and pressure to protect the delicate fetal villi
perfused by the low-pressure developing fetal circulation which are immersed in maternal blood
which circulates at a much higher pressure and velocity. Failure of the transformation of the spiral
arteries is associated with a number of common complications of pregnancy including
preeclampsia and fetal growth restriction.
The extravillous cytotrophoblast cells are involved in physiologically remodelling the maternal
spiral arteries which is completed by the end of the first trimester. After an apparent rest phase of
a couple of weeks (weeks 1416), there is a resurgence of the endovascular trophoblastic
migration. The second wave of cytotrophoblast cells moves down the myometrial segments of the
spiral arteries to their origin at the branching from the radial arteries. The cytotrophoblast cells are
involved with the destruction of the maternal artery musculoelastic tissue and the replacement of
the maternal endothelial wall with trophoblast resulting in a change in the vessel wall
vasoresponsiveness. The result is conversion of the thick-walled muscular spiral arteries to
compliant dilated sac-like uteroplacental vessels that have low impedance to blood flow.
The remodelled vessels can passively dilate and accommodate a greatly increased blood
flow (about 30% of maternal cardiac output) but they are not responsive to vasoactive
agents. The effect of this interaction between the trophoblastic cells and the maternal blood
vessels is that a low-pressure, high-conductance vascular system is established, which
provides an adequate maternal blood flow to the placenta and thus a plentiful provision of
oxygen and nutrients to the fetus. The maternal uteroplacental circulatory system is mostly
complete by mid-gestation. In contrast, the fetal villous tree continues to branch and develop
throughout the pregnancy, ensuring that the capacity of the placenta matches the growth of
the fetus.