Implantation (human embryo)

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Fertilization in humans. The sperm and ovum unite through fertilization, creating a conceptus that (over the course of 8-9 days) will implant in the uterine wall, where it will reside over the course of 9 months. Human Fertilization.png
Fertilization in humans. The sperm and ovum unite through fertilization, creating a conceptus that (over the course of 8-9 days) will implant in the uterine wall, where it will reside over the course of 9 months.

In humans, implantation is the stage of pregnancy at which the embryo adheres to the wall of the uterus. At this stage of prenatal development, the conceptus is called a blastocyst. It is by this adhesion that the embryo receives oxygen and nutrients from the mother to be able to grow.

Pregnancy time when children develop inside the mothers body before birth

Pregnancy, also known as gestation, is the time during which one or more offspring develops inside a woman. A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy can occur by sexual intercourse or assisted reproductive technology. Childbirth typically occurs around 40 weeks from the last menstrual period (LMP). This is just over nine months, where each month averages 31 days. When measured from fertilization it is about 38 weeks. An embryo is the developing offspring during the first eight weeks following fertilization, after which, the term fetus is used until birth. Symptoms of early pregnancy may include missed periods, tender breasts, nausea and vomiting, hunger, and frequent urination. Pregnancy may be confirmed with a pregnancy test.

Uterus major female hormone-responsive reproductive sex organ of most mammals including humans

The uterus or womb is a major female hormone-responsive secondary sex organ of the reproductive system in humans and most other mammals. In the human, the lower end of the uterus, the cervix, opens into the vagina, while the upper end, the fundus, is connected to the fallopian tubes. It is within the uterus that the fetus develops during gestation. In the human embryo, the uterus develops from the paramesonephric ducts which fuse into the single organ known as a simplex uterus. The uterus has different forms in many other animals and in some it exists as two separate uteri known as a duplex uterus.

Prenatal development includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal development until birth.

Contents

In humans, implantation of a fertilized ovum is most likely to occur around 9 days after ovulation, however this can range between 6 and 12 days. [1]

Human fertilization How babies Are Created

Human fertilization is the union of a human egg and sperm, usually occurring in the ampulla of the fallopian tube. The result of this union is the production of a zygote cell, or fertilized egg, initiating prenatal development. Scientists discovered the dynamics of human fertilization in the nineteenth century.

Ovulation The release of a mature ovum/oocyte from an ovary.

Ovulation is the release of eggs from the ovaries. In humans, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized by sperm. In addition, the uterine lining (endometrium) is thickened to be able to receive a fertilized egg. If no conception occurs, the uterine lining as well as blood will be shed during menstruation.

Implantation window

The reception-ready phase of the endometrium of the uterus is usually termed the "implantation window" and lasts about 4 days. The implantation window occurs around 6 days after the peak in luteinizing hormone levels. With some disparity between sources, it has been stated to occur from 7 days after ovulation until 9 days after ovulation, [2] or days 6-10 postovulation. [3] On average, it occurs during the 20th to the 23rd day after the last menstrual period. [4]

Endometrium inner mucous membrane of the mammalian uterus

The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer; the functional layer thickens and then is shed during menstruation in humans and some other mammals, including apes, Old World monkeys, some species of bat, and the elephant shrew. In most other mammals, the endometrium is reabsorbed in the estrous cycle. During pregnancy, the glands and blood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming the placenta, which supplies oxygen and nutrition to the embryo and fetus. The speculated presence of an endometrial microbiota has been argued against.

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. In females, an acute rise of LH triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with FSH.

The implantation window is characterized by changes to the endometrium cells, which aid in the absorption of the uterine fluid. These changes are collectively known as the plasma membrane transformation and bring the blastocyst nearer to the endometrium and immobilize it. During this stage the blastocyst can still be eliminated by being flushed out of the uterus. Scientists have hypothesized that the hormones cause a swelling that fills the flattened out uterine cavity just prior to this stage, which may also help press the blastocyst against the endometrium. [5] The implantation window may also be initiated by other preparations in the endometrium of the uterus, both structurally and in the composition of its secretions.

Blastocyst

The blastocyst is a structure formed in the early development of mammals. It possesses an inner cell mass (ICM) which subsequently forms the embryo. The outer layer of the blastocyst consists of cells collectively called the trophoblast. This layer surrounds the inner cell mass and a fluid-filled cavity known as the blastocoel. The trophoblast gives rise to the placenta. The name "blastocyst" arises from the Greek βλαστός blastos and κύστις kystis.

Adaptation of uterus

To enable implantation, the uterus goes through changes in order to be able to receive the conceptus.

Predecidualization

The endometrium increases thickness, becomes vascularized and its glands grow to be tortuous and boosted in their secretions. These changes reach their maximum about 7 days after ovulation.

Angiogenesis blood vessel formation when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Furthermore, the surface of the endometrium produces a kind of rounded cells, which cover the whole area toward the uterine cavity. This happens about 9 to 10 days after ovulation. [6] These cells are called decidual cells, which emphasises that the whole layer of them is shed off in every menstruation if no pregnancy occurs, just as leaves of deciduous trees. The uterine glands, on the other hand, decrease in activity and degenerate around 8 to 9 days [6] after ovulation in absence of pregnancy.

Menstruation Regular discharge of blood and tissue from the inner lining of the uterus through the vagina

Menstruation, also known as a period or monthly, is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The first period usually begins between twelve and fifteen years of age, a point in time known as menarche. However, periods may occasionally start as young as eight years old and still be considered normal. The average age of the first period is generally later in the developing world, and earlier in the developed world. The typical length of time between the first day of one period and the first day of the next is 21 to 45 days in young women, and 21 to 31 days in adults. Bleeding usually lasts around 2 to 7 days. Menstruation stops occurring after menopause, which usually occurs between 45 and 55 years of age. Periods also stop during pregnancy and typically do not resume during the initial months of breastfeeding.

The decidual cells originate from the stromal cells that are always present in the endometrium. However, the decidual cells make up a new layer, the decidua. The rest of the endometrium, in addition, expresses differences between the luminal and the basal sides. The luminal cells form the zona compacta of the endometrium, in contrast to the basalolateral zona spongiosa, which consists of the rather spongy stromal cells. [6]

Decidualization

Decidualization succeeds predecidualization if pregnancy occurs. This is an expansion of it, further developing the uterine glands, the zona compacta and the epithelium of decidual cells lining it. The decidual cells become filled with lipids and glycogen and take the polyhedral shape characteristic for decidual cells.

Trigger

It is likely that the blastocyst itself makes the main contribution to this additional growing and sustaining of the decidua. An indication of this is that decidualization occurs at a higher degree in conception cycles than in nonconception cycles. [6] Furthermore, similar changes are observed when giving stimuli mimicking the natural invasion of the embryo. [6]

Parts of decidua

The decidua can be organized into separate sections, although they have the same composition.

  • Decidua basalis - This is the part of the decidua which is located basalolateral to the embryo after implantation.
  • Decidua capsularis - Decidua capsularis grows over the embryo on the luminal side, enclosing it into the endometrium. It surrounds the embryo together with decidua basalis.
  • Decidua parietalis - All other decidua on the uterine surface belongs to decidua parietalis.

Decidua throughout pregnancy

After implantation the decidua remains, at least through the first trimester. [6] However, its most prominent time is during the early stages of pregnancy, during implantation. Its function as a surrounding tissue is replaced by the definitive placenta. However, some elements of the decidualization remain throughout pregnancy. [6]

The compacta and spongiosa layers are still observable beneath the decidua in pregnancy. The glands of the spongiosa layer continue to secrete during the first trimester, when they degenerate. However, before that disappearance, some glands secrete unequally much. This phenomenon of hypersecretion is called the Arias-Stella phenomenon, [6] after the pathologist Javier Arias-Stella.

Pinopodes

Pinopodes are small, finger-like protrusions from the endometrium. They appear between day 19 and day 21 [6] of gestational age. This corresponds to a fertilization age of approximately 5 to 7 days, which corresponds well with the time of implantation. They only persist for 2 to 3 days. [6] The development of them is enhanced by progesterone but inhibited by estrogens.

Function in implantation

Pinopodes endocytose uterine fluid and macromolecules in it. By doing so, the volume of the uterus decreases, taking the walls closer to the embryoblast floating in it. Thus, the period of active pinocytes might also limit the implantation window. [6]

Function during implantation

Pinopodes continue to absorb fluid, and removes most of it during the early stages of implantation.

Adaptation of secretions

proteins, glycoproteins and peptides

secreted by the endometrial glands [6]

Matrix-associated:
Fibronectin
Laminin
Entactin
Type-IV collagen
heparan sulfate
Proteoglycan
Integrins
-
Others:
Mucins
Prolactin
IGFBP-1
Placental protein 14 (PP14) or glycodelin
Pregnancy-associated endometrial

alpha-2-globulin (alpha-2-PEG)

endometrial protein 15
Albumin
Beta-Lipoprotein
Relaxin
Fibroblast growth factor 1
Fibroblast growth factor 2
Pregnancy-associated plasma protein A

(PAPP-A)

Stress response protein 27 (SRP-27)
CA-125
Beta-endorphin
Leu-enkephalin
Diamine oxidase
Tissue plasminogen activator
Renin
Progesterone-dependent carbonic anhydrase
Lactoferrin

Not only the lining of the uterus transforms, but in addition, the secretion from its epithelial glands changes. This change is induced by increased levels of progesterone from the corpus luteum. The target of the secretions is the embryoblast, and has several functions on it.

Nourishment

The embryoblast spends approximately 72 hours [6] in the uterine cavity before implanting. In that time, it cannot receive nourishment directly from the blood of the mother, and must rely on secreted nutrients into the uterine cavity, e.g. iron [6] and fat-soluble vitamins. [6]

Growth and implantation

In addition to nourishment, the endometrium secretes several steroid-dependent proteins, [6] important for growth and implantation. Cholesterol [6] and steroids [6] are also secreted. Implantation is further facilitated by synthesis of matrix substances, adhesion molecules and surface receptors for the matrix substances.

Mechanism

Implantation is initiated when the blastocyst comes into contact with the uterine wall.

Zona hatching

To be able to perform implantation, the blastocyst first needs to get rid of its zona pellucida. This process can be called "hatching".

Factors

Lytic factors in the uterine cavity, as well as factors from the blastocyst itself are essential for this process. Mechanisms in the latter are indicated by that the zona pellucida remains intact if an unfertilized egg is placed in the uterus under the same conditions. [6] A substance probably involved is plasmin. Plasminogen, the plasmin precursor, is found in the uterine cavity, and blastocyst factors contribute to its conversion to active plasmin. This hypothesis is supported by lytic effects in vitro by plasmin. [6] Furthermore, plasmin inhibitors also inhibit the entire zona hatching in rat experiments. [6]

Apposition

The very first, albeit loose, connection between the blastocyst and the endometrium is called the apposition. [6]

Location

On the endometrium, the apposition is usually made where there is a small crypt in it, perhaps because it increases the area of contact with the rather spherical blastocyst.

On the blastocyst, on the other hand, it occurs at a location where there has been enough lysis of the zona pellucida to have created a rupture to enable direct contact between the underlying trophoblast and the decidua of the endometrium. [6] However, ultimately, the inner cell mass, inside the trophoblast layer, is aligned closest to the decidua. Nevertheless, the apposition on the blastocyst is not dependent on if it is on the same side of the blastocyst as the inner cell mass. Rather, the inner cell mass rotates inside the trophoblast to align to the apposition. [6] In short, the entire surface of the blastocyst has a potential to form the apposition to the decidua.

Molecular Mechanism

The identity of the molecules on the trophoblast and the endometrial epithelia that mediate the initial interaction between the two remain unidentified. However, a number of research groups have proposed that MUC1, a member of the Mucin family of glycosylated proteins, is involved. [7] MUC1 is a transmembrane glycoprotein expressed at the apical surface of endometrial epithelial cells during the window of implantation in humans and has been shown to be differentially expressed between fertile and infertile subjects during this time. [7] MUC1 displays carbohydrate moieties on its extracellular domain that are ligands of L-selectin, a protein expressed on the surface of trophoblast cells. [8] An in vitro model of implantation developed by Genbacev et al., gave evidence to support the hypothesis that L-selectin mediates apposition of the blastocyst to the uterine epithelium by interacting with its ligands. [9]

Adhesion

Adhesion is a much stronger attachment to the endometrium than the loose apposition.

The trophoblasts adhere by penetrating the endometrium, with protrusions of trophoblast cells.

Communication

There is massive communication between the blastocyst and the endometrium at this stage. The blastocyst signals to the endometrium to adapt further to its presence, e.g. by changes in the cytoskeleton of decidual cells. This, in turn, dislodges the decidual cells from their connection to the underlying basal lamina, which enables the blastocyst to perform the succeeding invasion. [6]

This communication is conveyed by receptor-ligand-interactions, both integrin-matrix and proteoglycan ones.

Proteoglycan Receptors

Another ligand-receptor system involved in adhesion is proteoglycan receptors, found on the surface of the decidua of the uterus. Their counterparts, the proteoglycans, are found around the trophoblast cells of the blastocyst. This ligand-receptor system also is present just at the implantation window. [6]

Invasion

Invasion is an even further establishment of the blastocyst in the endometrium.

Syncytiotrophoblasts

The protrusions of trophoblast cells that adhere into the endometrium continue to proliferate and penetrate into the endometrium. As these trophoblast cells penetrate, they differentiate to become a new type of cells, syncytiotrophoblast. The prefix syn- refers to the transformation that occurs as the boundaries between these cells disappear to form a single mass of many cell nuclei (a syncytium). The rest of the trophoblasts, surrounding the inner cell mass, are hereafter called cytotrophoblasts.

Invasion continues with the syncytiotrophoblasts reaching the basal membrane beneath the decidual cells, penetrating it and further invading into the uterine stroma. Finally, the whole embryo is embedded in the endometrium. Eventually, the syncytiotrophoblasts come into contact with maternal blood and form chorionic villi. This is the initiation of forming the placenta.

Secretions

The blastocyst secretes factors for a multitude of purposes during invasion. It secretes several autocrine factors, targeting itself and stimulating it to further invade the endometrium. [6] Furthermore, secretions loosen decidual cells from each other, prevent the embryo from being rejected by the mother, trigger the final decidualization and prevent menstruation.

Autocrine

Human chorionic gonadotropin is an autocrine growth factor for the blastocyst. [6] Insulin-like growth factor 2, [6] on the other hand, stimulates the invasiveness of it.

Dislodging

The syncytiotrophoblasts dislodges decidual cells in their way, both by degradation of cell adhesion molecules linking the decidual cells together as well as degradation of the extracellular matrix between them.

Cell adhesion molecules are degraded by syncytiotrophoblast secretion of Tumor necrosis factor-alpha. This inhibits the expression of cadherins and beta-catenin. [6] Cadherins are cell adhesion molecules, and beta-catenin helps to anchor them to the cell membrane. Inhibited expression of these molecules thus loosens the connection between decidual cells, permitting the syncytotrophoblasts and the whole embryo with them to invade into the endometrium.

The extracellular matrix is degraded by serine endopeptidases and metalloproteinases. Examples of such metalloproteinases are collagenases, gelatinases and stromelysins. [6] These collagenases digest Type-I collagen, Type-II collagen, Type-III collagen, Type-VII collagen and Type-X collagen. [6] The gelatinases exist in two forms; one digesting Type-IV collagen and one digesting gelatin. [6]

Immunosuppressive

The embryo differs from the cells of the mother, and would be rejected as a parasite by the immune system of the mother if it didn't secrete immunosuppressive agents. Such agents are Platelet-activating factor, human chorionic gonadotropin, early pregnancy factor, immunosuppressive factor, Prostaglandin E2, Interleukin 1-alpha, Interleukin 6, interferon-alpha, leukemia inhibitory factor and Colony-Stimulating Factor.

Decidualization

Factors from the blastocyst also trigger the final formation of decidual cells into their proper form. In contrast, some decidual cells in the proximity of the blastocyst degenerate, providing nutrients for it. [6]

Prevention of menstruation

Human chorionic gonadotropin (hCG) not only acts as an immunosuppressive, [6] but also "notifies" the mother's body that she is pregnant, preventing menstruation by sustaining the function of the corpus luteum.

Other factors

Other factors secreted by the blastocyst are;

Failure

Implantation failure is considered to be caused by inadequate uterine receptivity in two-thirds of cases, and by problems with the embryo itself in the other third. [11]

Inadequate uterine receptivity may be caused by abnormal cytokine and hormonal signaling as well as epigenetic alterations. [12] Recurrent implantation failure is a cause of female infertility. Therefore, pregnancy rates can be improved by optimizing endometrial receptivity for implantation. [12] Evaluation of implantation markers may help to predict pregnancy outcome and detect occult implantation deficiency. [12]

Luteal support is the administration of medication, generally progestins, for the purpose of increasing the success rate of implantation and early embryogenesis, thereby complementing the function of the corpus luteum.

In women with more than 3 implantation failures in assisted reproduction, a review of several small randomized controlled studies estimated that the use of adjunct low molecular weight heparin (LMWH) improves live birth rate by approximately 80%. [13]

See also

Related Research Articles

Pregnancy (mammals) period of reproduction during which a female mammal carries one or more live offspring from implantation in the uterus through gestation

In mammals, pregnancy is the period of reproduction during which a female carries one or more live offspring from implantation in the uterus through gestation. It begins when a fertilized zygote implants in the female's uterus, and ends once it leaves the uterus.

Chorion

The chorion is the outermost fetal membrane around the embryo in mammals, birds and reptiles. It develops from an outer fold on the surface of the yolk sac, which lies outside the zona pellucida, known as the vitelline membrane in other animals. In insects it is developed by the follicle cells while the egg is in the ovary.

Corpus luteum Corpora leutia

The corpus luteum is a temporary endocrine structure in female ovaries and is involved in the production of relatively high levels of progesterone, moderate levels of estradiol and inhibin A, and small amounts of estrogen. It is the remains of the ovarian follicle that has released a mature ovum during a previous ovulation.

Female reproductive system reproductive system of the human female, made up of internal and external organs

The female reproductive system is made up of the internal and external sex organs that function in reproduction of new offspring. In the human the female reproductive system is immature at birth and develops to maturity at puberty to be able to produce gametes, and to carry a foetus to full term. The internal sex organs are the uterus, Fallopian tubes, and ovaries. The uterus or womb accommodates the embryo which develops into the foetus. The uterus also produces vaginal and uterine secretions which help the transit of sperm to the Fallopian tubes. The ovaries produce the ova. The external sex organs are also known as the genitals and these are the organs of the vulva including the labia, clitoris, and vaginal opening. The vagina is connected to the uterus at the cervix.

Trophoblast cells forming the outer layer of a blastocyst

Trophoblasts are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg. This layer of trophoblasts is also collectively referred to as "the trophoblast", or, after gastrulation, the trophectoderm, as it is then contiguous with the ectoderm of the embryo.

Relaxin chemical compound

Relaxin is a protein hormone of about 6000 Da first described in 1926 by Frederick Hisaw.

Decidua

The decidua is the modified mucosal lining of the uterus known as the endometrium that forms in preparation for pregnancy. It is formed in a process called decidualization under the influence of progesterone. Endometrial cells become highly characteristic. The decidua forms the maternal part of the placenta and remains for the duration of the pregnancy. It is shed off during childbirth — hence why the term is used, "decidua" having the meaning of falling away, as in the word deciduous.

Syncytiotrophoblast

Syncytiotrophoblast is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nutrient circulation between the embryo and the mother. It is a unique tissue in that it is a multi-nucleated, terminally differentiated syncytium, extending to 13 cm.

Cytotrophoblast

The cytotrophoblast is the inner layer of the trophoblast. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embryo.

In embryology, Carnegie stages are a standardized system of 23 stages used to provide a unified developmental chronology of the vertebrate embryo.

L-selectin protein-coding gene in the species Homo sapiens

L-selectin, also known as CD62L, is a cell adhesion molecule found on leukocytes and the preimplantation embryo. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups. It is cleaved by ADAM17.

Decidualization The cellular and vascular changes occurring in the endometrium of the pregnant uterus just after the onset of blastocyst implantation. This process involves the proliferation and differentiation of the fibroblast-like endometrial stromal cells into l

Decidualization is a process that results in significant changes to cells of the endometrium in preparation for, and during, pregnancy. This includes morphological and functional changes to endometrial stromal cells (ESCs), the presence of decidual white blood cells (leukocytes), and vascular changes to maternal arteries. The sum of these changes results in the endometrium changing into a structure called the decidua. In humans, the decidua is shed during the third phase of birth.

Before the fertilized ovum reaches the uterus, the mucous membrane of the body of the uterus undergoes important changes and is then known as the decidua. The thickness and vascularity of the mucous membrane are greatly increased; its glands are elongated and open on its free surface by funnel-shaped orifices, while their deeper portions are tortuous and dilated into irregular spaces. The interglandular tissue is also increased in quantity, and is crowded with large round, oval, or polygonal cells, termed decidual cells. Their enlargement is due to glycogen and lipid accumulation in the cytoplasm allowing these cells to provide a rich source of nutrition for the developing embryo.

Human embryonic development process of cell division and cellular differentiation of the embryo that occurs during the early stages of development

Human embryonic development, or human embryogenesis, refers to the development and formation of the human embryo. It is characterised by the process of cell division and cellular differentiation of the embryo that occurs during the early stages of development. In biological terms, the development of the human body entails growth from a one-celled zygote to an adult human being. Fertilisation occurs when the sperm cell successfully enters and fuses with an egg cell (ovum). The genetic material of the sperm and egg then combine to form a single cell called a zygote and the germinal stage of development commences. Embryonic development in the human, covers the first eight weeks of development; at the beginning of the ninth week the embryo is termed a fetus. Human embryology is the study of this development during the first eight weeks after fertilisation. The normal period of gestation (pregnancy) is nine months or 38 weeks.

Hormonal regulation occurs at every stage of development. A milieu of hormones simultaneously affects development of the fetus during embryogenesis and the mother, including human chorionic gonadotropin (hCG) and progesterone (P4).

The plasma membrane transformation is a concept introduced by Christopher R. Murphy of The University of Sydney to encapsulate the idea that a series of changes in the plasma membrane of uterine epithelial cells is essential to the development of the receptivity of the uterus (womb) for attachment of the blastocyst and the beginning of a pregnancy.

The internal surface of the uterus is lined by uterine epithelial cells which undergo dramatic changes during pregnancy. The role of the uterine epithelial cells is to selectively allow the blastocyst to implant at a specific time. All other times of the cycle, these uterine epithelial cells are refractory to blastocyst implantation. Uterine epithelial cells have a similar structure in most species and the changes which occur in the uterine epithelial cells at the time of blastocyst implantation are also conserved among most species.

Repeated Implantation failure (RIF) is the failure of the embryo to implant onto the side of the uterus wall following IVF treatment. Regularly, this happens at 6-7 days after conception and involves the embedding of the growing embryo into the mothers uterus and a connection being formed. A successful implantation can be determined by using an ultrasound to view the sac which the baby grows in, inside the uterus.

References

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Further reading