willams ch. 7 fetal growth and development 부산백병원 산부인과 r2 박영미
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Willams ch. 7 Fetal growth and Development
부산백병원 산부인과R2 박영미
PHYSILOLGY OF THE FETUS
Amnionic fluid (1) Amnionic fluid is composed
In early pregnancy : ultrafiltrate of maternal plasma
Second trimester : extracellular fluid which diffuses through the fetal ski
n
After 20weeks : fetal urine : the fetal kidneys start producing urine at 12wks, by 1
8wks are producing 7-14ml/d
Amnionic fluid (2) Amnionic fluid volume
Increaes by 10ml per week at 8weeks and up to 60ml per week at 21weeks Declines gradually back to a steady state by 33week
s
The usual amnionic volume 50ml at 12weeks 400ml at midpregnancy 1000ml at term
Amnionic fluid (3) Amnionic fluid serves to
Cushion – allowing musculoskeletal development Protecting from trauma Maintains temperature Minimal nutritive function
Epidermal growth factor, EGF-like growth factors (transforming growth factor-α) Ingestion of amnionic fluid into the lung and gastroint
estinal tract -> promote growth and differentiation of these tissues
Fetal circulation (1) Oxygenated blood is brought to the fetus by the umbilical
vein
The vein divides into the ductus venosus and the portal sinus
The ductus venosus is enter the inferior vena cava directly It carries well-oxygenated blood directly to the heart
The portal sinus carries blood to the hepatic veins
Relatively deoxygenated blood from the liver then flows back into the inferior vena cava
Fetal circulation (2)
Fetal circulation (3)
The ventricles of the fetal heart work in parallel, not in series
Well-oxygenated blood enters the left ventricle through the foramen ovale -> supplies the heart and brain
Less oxygenated blood enters the right ventricle through the tricuspid valve -> supplies the rest of the body
Fetal circulation (4)
Two separate circulations
by the structure of the right atrium depending on its oxygen content
The well-oxygenated blood -> along the medial aspect of the inferior vena cava
The less oxygenated blood -> along the lateral vessel wall
Fetal circulation (5) About 87% of blood exiting the right ventricle -> the ductus arteriosus -> descending aorta
only 13% of right ventricular output -> to the lung
The high pulmonary vascular resistance Lower resistance in the ductus arteriosus
One third of the blood passing through the ductus arteriosus -> to the body
The remaining output -> return to the placenta through the two hypogastric arteries -> distally become the umbilical arteries
Fetal blood (1) Hemopoiesis
Fetal blood (2) As fetal development progresses :
1. circulating erythrocytes are smaller and nonnucleated The first erythrocytes : nucleated,macrocytic
2. the volume of blood in the common fetoplacental circulation increase
3. Hemoglobin concentration rises Midpregnancy : 12g/dL By term : 18g/dL
Fetal blood (3)
Erythropoiesis
Controlled by erythropoietin made by the fetus Maternal erythropoietin does not cross the placenta
Produced in response to hypoxic stress Bleeding, labor, isoimmunization
Influenced by testosterone, estrogen, prostaglandins, thyroid hormone, lipoproteins
Fetal liver – may be an important source until renal production begins
Fetal blood (4) Fetal blood volume
Blood volume of term normal infants : average of 78 mL/kg when cord-clamping
The blood volume of fetal origin in the placenta : average 45 mL/kg
Fetoplacental blood volume at term : approximately 125 mL/kg
Fetal blood (5) Fetal hemoglobin
During embryonic and fetal life, a variety of a and b chain precursors
The timing of the production of each of these early hemoglobin version corresponds to the site of hemoglobin production Yolk sac : hemoglobin Gower 1, Gower 2, Portland Liver : hemoglobin F Bone marrow : normal hemoglobin A
Fetal blood (6)
The switch : various embryonic Hb -> Hb A methylation of the early globin genes
Diabetic women Persistence of Hb F Hypomethylation of the r-gene
Sickle cell anemia r-gene remains unmethylated Large quantities of fetal Hb
Fetal blood (7)
Hb F bind more oxygen than Hb A
Hb A binds 2,3-DPG more avidly than Hb F : lowers the affinity of Hb A for oxygen
Lower concentration of 2.3-DPG of fetal Hb : increased oxygen affinity of the fetal erythrocyte
The amount of Hb F in fetal erythrocytes falls during the latter weeks of pregnancy At term, about ¾ of the total Hb is Hb F
Fetal blood (8) Coagulation factors in the fetus
About 12 weeks Normal, adult-type, procoagulant, fibrinolytic, anticoagulant
proteins at appreciably reduced levels not cross the placenta
Factors : II, VII, IX, X, XI, XII, XIII, fibrinogen
Fetal fibnogen as early as 5 weeks differenet properites -> less compressible clot, lower degree aggregation compared with adult
Fetal blood (9)
Despite this reduced coagulation factors, the fetus seems to be protected from hemorrhage, and fetal bleeding is a rare event Cordocentesis : amnionic fluid thromboplastins and some fa
ctor in Wharton jelly combine to faciliate coagulation at the umbilical cord puncture site
Protein C, S, antithrombin III deficiency, or the Leiden (factor V) mutation : thrombosis, infarction
Stillbirth followed by maternal pulmonary embolism : protein S deficiency
Fetal blood (10) Fetal plasma proteins
Concentrations of plasma protein, albumin, lactic dehydrogenase, aspartate aminotransferase, r-glutamyl transpeptidase, alanine trasferase
-> all increase with gestational age
At birth, the mean total plasma protein, albumin concentrations in fetal blood
-> similar to maternal levels
Fetal blood (12)
Immunoglobulin G
IgG transport begins at about 16weeks
The bulk of IgG from the mother is during the last 4weeks of pregnancy Preterm infants : relatively poorly with maternal antibody
Adult values are not attained until 3years of age
Fetal blood (11) Immunocompetence of the fetus
In the absence of a direct antigenic stimulus (such as infection)
-> almost total immunoglobulins in the fetus is immunoglobulin G -> IgG synthesized in the maternal compartment and transferred across the placenta by receptor-mediated processes in syncytiotrophoblast
Fetal blood (13)
Immunoglobulin M
IgM is not transported from mother to ferus
Increased levels of IgM with congenital infection Rubella Cytomegalovirus Toxooplasmosis
Adult levels are attained by 9 months of age
Fetal blood (14)
Immunoglobulin A
IgA ingested in colostrum -> mucosal protection against enteric infection
IgA ingested with amnionic fluid before delivery
Fetal blood (15)
Lymphocytes
B lymphocytes : in liver by 9weeks : in blood & spleen by 12weeks
T lymphocytes : leave the thymus at 14weeks
The newborn responds poorly to immunization Deficient response of B cells to polyclonal activation Lake of T cell proliferation
Nervous system and sensory organs
The spinal cord extends In the embryo : entire vertebral column By 24 weeks : S1 At birth : L3 In the adult : L1
Myelination of the spinal cord Begins in the middle of gestation Continues through the first year of life
Synaptic function Developed by the eighth week
Nervous system and sensory organs
At 10 weeks Squinting Opening the mouth swallowing Incomplete finger closure
complete finger closure during the fourth lunar month
14-16 weeks Respiration
After 24 weeks The ability to suck
The third trimester Integration of nervous and muscular function proceeds
Nervous system and sensory organs
The development of internal, middle, external components of the ear -> by midpregnancy
The fetus hears some sounds in utero as early as 24-26 weeks
The eye sensitivity to light -> by 28 weeks
But, perception of form and color is not complete until long after birth
Gastrointestinal tract (1)
Swallowing begins at 10-12weeks Coincident with intestine peristalsis and glucose transport
What stimulates swallowing -> not clear The fetal neural analog of thirst Gastric emptying Change in the amnionic fluid composition Fetal taste buds
Late in pregnancy, the volume of amnionic fluid -> regulated by fetal swallowing Term fetus : 200-760mL per day
Gastrointestinal tract (2)
Movement of amnionic fluid through the gastrointestinal system Enhance growth and development of the alimentary canal
The swallowed amnionic fluid Contributes little to the caloric requirements Contributes essential nutrients Late in pregnancy, about 0.8g of soluble protein, approximately
half albumin, each day
Gastrointestinal tract (3) Meconium
Composition of meconium Undigested debris from swallowed amnionic fluid Glycerophospholipid from the lung Desquamated fetal cells Lanugo Scalp hair Vernix
Meconium passage Normal bowel peristalsis in the mature fetus Vagal stimulation due to cord compression Hypoxia -> arginine vasopressin -> stimulates the smooth m
uscle of the colon to contract
Gastrointestinal tract (4)
Liver liver enzyme levels increase with gestational age
Limited capacity for converting free bilirubin to bilirubin diglucuronoside Most of the bilirubin is transferred to the maternal circulatio
n through the placenta The small fraction conjugated bilirubin -> excreted through th
e biliary tract into the intestine Unconjugated bilirubin -> excreted into the amnionic fluid aft
er 12weeks -> transferred across the placent
Gastrointestinal tract (5)
Most of the cholesterol -> produced in fetal liver
Glycogen Second trimester : low concentration in fetal liver Near term : rapid and marked increase to levels
two- three times those in adult liver
Gastrointestinal tract (6)
Pancreas 9-10weeks : Insulin-containing granules 12weeks : insulin in fetal plasma
hyperglycemia -> increasing plasma insulin Newborns of diabetic mothers Large for gestational age infants
14weeks : amylase in amnionic fluid 16weeks : Most pancreatic enzymes are present
Trypsin, Chymotrypsin, Phospholipase A, lipase
Urinary system (1)
2weeks : pronephros
5weeks : mesonephros -> producing urine
11-12weeks : mesonephros -> degeneration
9-12weeks : ureteric bud and nephrogenic blastema -> metanephros
14weeks : loop of Henle -> functional & reabsorption occurs
Until 36weeks : new nephrons
Urinary system (2) The kidney receive 2-4% of the cardiac output
Renal vascular resistance is high
The glomerular filtration fraction is low
The filtration rate increases with gestational age 12weeks : less than 0.1mL/min 20weeks : 0.3mL/min
Urine production start at 12weeks 18weeks : 7-14mL/day At term : 27mL/hr, 650mL/day
Pulmonary system (1) Anatomical maturation of the fetal lung
Pseudoglandular stage 15-17weeks The growth of the intrasegmental bronchial tree
Canalicular stage 16-25weeks The peripheral extension of bronchial cartilage plates terminal bronchiole -> respiratory bronchioles -> multiple saccular ducts
Terminal sac stage The alveoli -> primative pulmonary alveoli (terminal sac)
Pulmonary system (2) An extracellular matrix develops from proximal to dist
al lung segments until term
Extensive capillary network & lymph system develops
The type II cells start to produce surfactant
At birth, only 15% of the adult number of alveoli
The lung continues to grow, adding more alveoli up to about 8 years
Pulmonary system (3) Surfactant
Formed in the type II pneumonocytes Multivesicular bodies -> Lamellar bodies -> surfactant
At birth, with the first breath Air-to-tissue interface in the lung
alveolus Surfactant to uncoil from the la
mellar bodies Prevent alveolar collapse during
expiration
Pulmonary system (4)
Surfactant compositon
80% : Phosphatidylcholines (lecithins)
8-15% : phosphatidylglycerol
Reducing surface tension in the alveolus
Pulmonary system (5)
Corticosteroids and fetal lung maturation
Cortisol, produced in the fetal adrenal glands Natural stimulus for lung maturation Augmented surfactant synthesis
Glucocorticosteroids Administered in large amounts to the woman At certain critical times during gestation Effect an increase in the rate of fetal lung maturation
Pulmonary system (6)
Respiration
Respiratory muscles movement of fetal chest wall Detected by USG as early as 11weeks
Respiratory movement intense to move amnionic fluid in and out of the respiratory tract
At the fourth month
Endocrine glands (1)
Pituitary gland : The fetal pituitary develops from two different sources
Adenohypophysis From the oral ectoderm – Rathke pouch
Neurohypophysis From the neuroectoderm
Endocrine glands (2) Anterior pituitary
: differnetiates into five cell types : secrete six protein hormones
Lactotropes -> prolactin (PRL) Somatotropes -> growth hormone (GH) Corticotropes -> corticotropin (ACTH) Thyrotropes -> thyroid stimulating hormone (TSH) Gonadotropes -> luteinizing hormone (LH) -> follicle stimulating hormone (FSH)
: 7weeks -> ACTH is first detected : 17weeks -> synthesize and store all pituitary hormones
Endocrine glands (3)
Neurohypophysis
Well developed by 10-12weeks
Oxytocin, arginine vasopressin (AVP)
Conserve water by actions largely at the level of lung & placenta (rather than kidney)
Endocrine glands (4) Intermediate pituitary gland
Only in the fetal pituitary gland
Disappeared before term, absent in adult
a-melanocyte stimulating hormone (a-MSH)
b-endorphin
The levels of a-MSH decrease progressively with gestation
Endocrine glands (5) Thyroid
Hormone synthesis by 10-12weeks
The placenta actively concentrates iodide on the fetal side
The fetal thyroid concentrates iodide more avidly than the maternal thyroid Radioiodide, amount of ordinary iodide -> hazardous
Placental tissue and membranes Prevent substantial passage of maternal thyroid hormones t
o the fetus Rapidly deiodinating maternal T4 & T3 to reverse T3
Endocrine glands (6)
The role of thyroid hormone Normal development of virtually all fetal tissues, especially b
rain
Congenital hyperhyroidism When maternal thyroid-stimulating antibody crosses the plac
enta Tachycardia, hepatosplenomegaly, hematological abnormalit
ies, craniosynostosis, growth restriction
Endocrine glands (7)
Adrenal glands Fetal adrenal glands : much larger in relation to total
body size than in adults
Fetal zone of the adrenal cortex Hypertrophied fetal zone Involutes rapidly after birth
Aaldosterone Near term, the cord plasma levels exceed those in maternal
plasma Renal tubules : relatively insensitive to aldosterone
Fetal Gender
Sexual differentiation of the embryo-fetus
Gender differentiation is determined by
Chromosomal make-up
Gonad development
Phenotypic gender
Sexual differentiation of the embryo-fetus
Chromosomal sex Genetic sex, XX or XY At the time of fertilization of the ovum
Gonadal sex Primordial germ cells originate in the endoderm of th
e yolk sac -> migrate to the genital ridge -> form the indifferent gonad (ovary, testis)
Sexual differentiation of the embryo-fetus
Y chromosome At 6 weeks after conception
The gonad begins developing into a testis
Directed by a gene located on the short arm of Y
Testis-determining factor (TDF)
Sex-determining region (SRY)
The SRY gene is expressed in the human single-cell zygote immediately after ovum fertilization
Sexual differentiation of the embryo-fetus
Phenotypic sex Male phenotypic sexual differentiation
-> directed by the function of the fetal testis In the absence of the testis
-> female differentiation ensues The mullerian ducts
uterus, fallopian tubes, upper vagina The wolffian duct
epididymis, vas deferens, seminal vesicle Testosterone -> 5a-dihydrotestosterone
Act in Genital tubercle, labioscrotal folds -> penis, scrotum
Sexual differentiation of the embryo-fetus
Fetal testicular contributions to male sexual differentiation
Mullerian-inhibiting substance
Produced by the Sertoli cells of the seminiferous tubules
Secreted as early as 7 weeks
Regression of the mullerian duct
Prevent the development of uterus, fallopian tube, upper vagina
Mullerian duct regression is completed by 9-10weeks
Sexual differentiation of the embryo-fetus
Fetal testosterone secretion
Directly act on the wolffian duct
Development of the vas deferens, epididymidis, seminal vesicles
Converted to 5a-dihydrotestosterone in fetal blood
Amplifies the androgen action of testosterone
Virilization of the external genitalia
Sexual differentiation of the embryo-fetus
Genital ambiguity of the newborn
The abnormalities of sexual differentiation causing genital ambiguity can be assigned to one of four clinically defined categories
Female pseudohermaphroditism
Male pseudohermaphroditism
Dysgenetic gonads
True hermaphroditism
Category 1. female pseudohermaphroditism
Mullerian-inhibiting substance is not produced The uterus, fallopian tubes, upper vagina develop
Androgen exposure of the embryo-fetus is excessive, for a fetus destined to be female
Clitoral hypertrophy, posterior labial fusion Labioscrotal folds, development of a urogenital sinus Development of a penile urethra with scrotal formation
The karyotype is 46,XX
Ovaries are present
Category 1. Female Pseudohermaphroditism
The androgenic excess Congenital adrenal hyperplasia Transfer of androgen from the maternal compartment Drugs ingested in prgnancy
Congenital adrenal hyperplasia Life threatening, medical emergency Adrenal failure provokes nausea, vomiting, diarrhea,
dehydration, shock The neonate treated until appropriate tests confirm,
of rule it out
Category 2. Male Pseudohermaphroditism
Production of mullerian-inhibiting substance The uterus, fallopian tubes, upper vagina -> not develop
Incomplete but variable androgenic representation for a fetus destined to be male Inadequate production of testosterone by the testis Diminished responsiveness to normal quantities of androgen –
abnormal or absent androgen receptor protein Failure of the in situ formation of 5a-dihydrotestosterone in andr
ogen responsive tissue
The karyotype is 46, XY
The presence of testes or else no gonads
Category 3. Dysgenetic Gonads
Mullerian-inhibiting substance is not produced the uterus, fallopian tubes, upper vagina are present in all of th
e subjects of this category
Fetal androgen exposure is variable
The karyotype varies among subjects and is commonly abnormal
Neither normal ovaries nor testes are present-rarely, both ovarian and testicular tissues are found.
Category 3. Dysgenetic Gonads
Tuner syndrome (46X)
Most common form of dysgenesis
The phenotype is female
Secondary sex characteristics do not develop at the time of expected puberty
Sexual infantilism
Category 4. True Hermaphroditism
In most subjects, the guidelines for category 3 are met
In addition, both ovarian and testicular tissues are found
In particular, germ cells (ova and sperm) of both sexes are found in the abnormal gonads
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