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PartI

Conception and Conceptus Development

Early conceptus growth andimmunobiologic adaptations of pregnancyKenneth H.H. Wong and Eli Y. Adashi

Reproduction will only be successful if a multitude of intricate sequences and inter-actions occur. This reproductive process begins with the formation of individualmale and female gametes. Following gamete formation, a mechanism must be pro-vided to ensure that these gametes attain close proximity to each other so that fer-tilization may take place. After successful fertilization, the newly formed embryomust develop correctly and, finally, implant in a nourishing environment.

Fertilization

Embryonic development begins with the process of fertilization, the union of indi-vidual male and female gametes (Fig. 1.1). The fusion of two haploid cells, eachbearing 22 autosomes and one sex chromosome, creates an offspring whose geneticmakeup is different that of from both parents. Fertilization consists of a regulatedsequence of interactions that will ultimately result in embryo development (Fig. 1.2).

Preimplantation embryo

The initial phases of embryonic growth following fertilization are concerned withrapid cell division (Fig. 1.3). This initial increase in cell numbers is critical in estab-lishing a sufficient number of cells in the embryo, which can then initiate differen-tiation. These cells are known as blastomeres. Beginning with the first divisionapproximately 24–30 hours after fertilization, the blastomeres become smaller withsuccessive divisions. Approximately 3 days after fertilization, the berry-like mass ofcells, termed the morula, enters the uterus.

The next event in embryo development is the formation of a fluid-filled cavity,the blastocele. With blastocyst formation, there is a partitioning of cells between aninner cell mass, the embryoblast, and an outer mass of cells, the trophectoderm.After entering the uterus, the developing blastocyst floats inside the endometrialcavity for about 2–3 days. The embryo begins implantation approximately 6 days

Handbook of Clinical Obstetrics: The Fetus & Mother, Third EditionE. Albert Reece, John C. Hobbins

Copyright © 2007 by Blackwell Publishing Ltd

after fertilization, while the primitive germ layers develop between days 6 and 8.Following initial implantation, the embryo is completely imbedded within theendometrium by approximately 8–9 days after ovulation. Immediately followingadhesion, the blastocyst begins penetration into the endometrial epithelium andstroma (Fig. 1.4).

Immunobiologic adaptations of pregnancy

The primary role of the immune system is to protect the body from invasion byforeign organisms and their toxic products. This requires an ability to discriminatebetween self and nonself antigens, so that immune destruction can be targetedagainst the invading organism and not against the animal’s own tissues. In preg-nancy, the antigenically foreign fetus grows in its mother for 9 months, unharmed

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Figure 1.1 Fertilization. A sperm is shown penetrating an oocyte. The spermatozoon mustfirst undergo capacitation. Next, the sperm must penetrate the cumulus (the investment ofcells and matrix surrounding the oocyte). After cumulus penetration, the sperm binds to the zona pellucida via specific receptors. The plasma membranes of the sperm and oocytefuse. The sperm and tail of the sperm enter the oocyte, leaving the sperm’s plasmamembrane.

by her immune system. Clearly, immune adaptations must occur in pregnancy thatare central to the survival of the fetus while maintaining the mother’s ability to fightinfection.

Immune circuit

It is clear from the foregoing discussion that, in normal pregnancy, fetal growth pro-gresses side by side with the development of a number of immune mechanisms thatfunction at several levels. These can be summarized by constructing an immunecircuit (Fig. 1.5A). The first stage in this circuit is the exposure of the maternal

EARLY CONCEPTUS GROWTH AND IMMUNOBIOLOGICAL ADAPTATIONS

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Figure 1.2 Proposed sequence for mammalian gamete interaction. ZP, zona pellucida.(Adapted from ref. 35, with permission.)

immune system to both fetal trophoblast and leukocytes. This could potentially leadto immune recognition and the development of cell-mediated and antibodyresponses to fetal antigens, which in turn would lead to rejection of the fetus (pla-centa). However, this circuit is broken at several stages (Fig. 1.5B). First, on thebasis of current evidence, the maternal immune system does not recognize the tro-phoblast because it either fails to express HLA or expresses HLA-G. Second,although fetal leukocytes can be recognized by maternal immune cells, only anti-body responses occur because the placenta’s production of Th2 cytokines down-regulates cell-mediated immunity. Finally, the production of antipaternal antibodiesis not harmful because the placenta filters out these antibodies before they reach thefetal circulation. Thus, it is the combination of these many immune adaptations ofpregnancy that ensures the success of the fetus.

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Figure 1.3 Cleavage and blastogenesis. Cleavage occurs in stages and results in theformation of blastomeres. The morula is composed of 12–16 blastomeres. The blastocystforms when approximately 60 blastomeres are present. Note that the zona pellucida hasdisappeared by the late blastocyst stage. Until the zona pellucida is shed, the developingembryo essentially does not increase in size.

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EARLY CONCEPTUS GROWTH AND IMMUNOBIOLOGICAL ADAPTATIONS

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Figure 1.5 (A) Immune responses in pregnancy that could lead to rejection of the fetus. (B) Immunoregulatory mechanisms in pregnancy that prevent the rejection of the fetus.

Further reading

Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive endocrinology, surgery and technol-ogy. Philadelphia, PA: Lippincott-Raven, 1996.

Creasy RK, Resnik R, Iams J, eds. Maternal–fetal medicine, 5th edn. Philadelphia, PA: W.B.Saunders, 2004.

Knobil E, Neill JD, eds. The physiology of reproduction, 2nd edn. New York: Raven Press,1994.

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2 Normal embryonic and fetal developmentTrivedi Vidhya N. Persaud and Jean C. Hay

Fertilization normally occurs in the ampulla of the uterine tube and results in theformation of a zygote. The zygote undergoes cleavage, forming blastomeres. Themorula, composed of approximately 16 blastomeres, enters the uterine cavity,forming a blastocyst consisting of the outer cell mass or trophoblast and the innercell mass or embryoblast. As the blastocyst implants in the endometrium, the tro-phoblast differentiates into the syncytiotrophoblast and cytotrophoblast and, by theend of this week, the hypoblast appears. During the second week, implantation iscompleted, and a bilaminar embryonic disk of epiblast and hypoblast is formed.The primary yolk sac becomes the secondary or definitive yolk sac as hypoblast cellsgrow out and line it. The trilaminar embryonic disk is formed during the third week,differentiation of the germ layers begins, and a primitive circulatory system is estab-lished. Epiblast cells from the primitive streak pass between the epiblast and thehypoblast to form intraembryonic mesoderm. The epiblast is now called the embry-onic ectoderm. The primitive node also gives rise to the notochord. Embryonicmesoderm passes between the ectoderm and the endoderm except at the oropha-ryngeal and cloacal membranes, and where the notochord is located. The primitivestreak will regress and disappear.

The notochord and adjacent mesoderm induce the overlying ectoderm to formthe neural plate, which gives rise to neural folds. The neural folds fuse to form theneural tube with a central neural canal, the anterior neuropore (closes between days25 and 26 of gestation), and the posterior neuropore (closes by day 28). Intraem-bryonic mesoderm forms the somites. A somite is composed of a dermatome, whichcontributes to the dermis, a myotome, which gives rises to skeletal muscle, and asclerotome, the precursors of the vertebrae and the ribs. Finally, it forms the lateralmesoderm in which spaces develop and coalesce, forming a horseshoe-shapedintraembryonic coelom, which gives rise to the pericardial, pleural, and peritonealcavities. This coelom splits the lateral mesoderm into a somatic and a splanchnic